Riluzole prodrugs and their use

ABSTRACT

Pharmaceutical compositions of the invention include substituted riluzole prodrugs useful for the treatment of cancers including melanoma, breast cancer, brain cancer, and prostate cancer through the release of riluzole. Prodrugs of riluzole have enhanced stability to hepatic metabolism and are delivered into systemic circulation by oral administration, and then cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.16/689,150 filed Nov. 20, 2019, which is a continuation of U.S.application Ser. No. 16/449,948 filed Jun. 24, 2019 issued as U.S. Pat.No. 10,905,681 on Feb. 2, 2021, which is a continuation of U.S.application Ser. No. 15/549,154 filed Aug. 5, 2017 issued as U.S. Pat.No. 10,485,791 on Nov. 26, 2019, which is a national stage applicationunder 35 U.S.C. § 371 of international application No.PCT/US2016/019787, filed Feb. 26, 2016, which claims priority to and thebenefit of U.S. Provisional Application No. 62/127,684 filed Mar. 3,2015, all of which are herein incorporated by reference in theirentireties.

STATEMENT OF FEDERALLY FUNDED RESEARCH

This invention was made with government support under grant numbers R43CA156781 and R44 CA156781 awarded by the National Institutes of Health.The government has certain rights in the invention.

FIELD OF INVENTION

The present invention describes compounds and methods useful as prodrugagents, useful for the treatment of cancers including melanoma throughthe release of riluzole.

BACKGROUND OF THE INVENTION

A recently conducted Phase 0 human clinical trial of riluzole (Rilutek™)demonstrated dramatic efficacy in certain melanoma patients after only14 days of treatment. Riluzole, the only FDA approved drug to treatamyotrophic lateral sclerosis (ALS), showed clinical or radiologicevidence of tumor response in four of 12 patients with Stage III and IVmelanoma, cancer with a poor prognosis and severely limited treatmentoptions.

The use of riluzole (RILUTEK®) for cancers or other diseases issignificantly constrained due to high levels of variability in hepaticmetabolism of the drug, dose dependent effects on the liver, and anegative food effect associated with the drug when administered withmeals. The approved USPI notes that that riluzole tablets should betaken at least 1 hour before, or 2 hours after, a meal to avoidfood-related decreases in bioavailability that may interfere with theability to achieve or maintain therapeutic blood concentrations. Suchfasting requirements amount to six hours of fasting per day whenadministered twice daily. Despite riluzole's approval over 20 years ago,these multiple clinical constraints of riluzole have persisted andlimited the clinical application of riluzole to other disease states. Wedescribe here prodrugs of riluzole in order to improve the clinicalefficacy of riluzole-based therapy, increase patient compliance, andrelieve human suffering. Metastatic melanoma has few treatment options,and the current therapeutic standard of

care is dacarbazine which is a highly cytotoxic drug with severe sideeffects including vomiting, headache and hair loss. Treatment withdacarbazine has a median progression-free enhancement of survival timeof only 1.5 months. Riluzole (Rilutek™) is a generally non-toxic drugand currently the only FDA-approved treatment for amyotrophic lateralsclerosis (ALS or Lou Gehrig's disease). We have recently shown thatriluzole has dramatic anti-melanoma activity in vitro cellular assays,in mice and in a Phase 0 human clinical trial. In the clinic, four oftwelve melanoma patients showed significant clinical or radiologicevidence of Stage III and IV tumor response. These results, along withthe mild side-effect profile that riluzole has shown among ALS patients,suggests that this drug has significant potential for use as an improvedtreatment for metastatic melanoma. However, the therapeutic utility ofriluzole itself in ALS and eventually for melanoma is very constrainedby rapid first-pass metabolism in the liver and an exceptionally highlevel of patient-to-patient variability in the extent of theCyp1A2-mediated oxidative metabolism that is observed.

Riluzole is also believed to be clinically relevant in additionaldisease states, including a variety of central nervous system (“CNS”)and depression/anxiety states. These include, but are not limited to,bipolar disorder, treatment resistant and major depression,obsessive-compulsive disorder, general anxiety disorder, panic disorder,social anxiety, mood disorders, cognitive disorders, dementia,agitation, apathy, psychoses, post-traumatic stress disorders,irritability, disinhibition, learning disorders, memory loss,personality disorders, bipolar disorders, Rett syndrome, eatingdisorders, conduct disorder, neurodegenerative disorders, paindisorders, supranuclear palsy, frontotemporal dementia, frontotemporallobar degeneration, delirium, Alzheimer's disease, mild Alzheimer'sdisease, mild cognitive impairment, mild cognitive impairment due toAlzheimer's disease, drug addiction, tinnitus, mental retardation,spinal muscular atrophy, radiation therapy, multiple sclerosis, chroniccerebellar ataxia, hereditary spinocerebellar ataxia, spinocerebellarataxia, sporadic ataxia, episodic ataxia, Friedreich Ataxia, MultisystemAtrophy, ataxia associated with Anti-GAD antibodies target andonconeural antigen, essential tremor, cervical spondylotic myelopathy,spinal cord injury, hereditary cerebellar ataxia, Tourette syndrome,autism spectrum disorder, schizophrenia, fragile X syndrome, Parkinson'sDisease, Progressive Supranuclear Palsy, Dementia with Lewy Bodies, andHuntington's disease. However, riluzole can have issues in livermetabolism. Pro-drugs of riluzole will provide more predictablepharmacokinetic properties and metabolic profiles for the parentcompound, leading to an improved therapeutic effect in each of theaforementioned disease states. Riluzole has been approved for 25 yearswithout solutions to the pharmacokinetic and metabolic limitations ofthe drug. The intrinsic property of the drug itself teaches away fromthe sublingual administration of riluzole. Riluzole has a very lowsolubility in water, poor oral palatability, pH dependent chemicalstability, and intense as well as persistent numbness or burningsensation throughout the oral cavity. Techniques aimed at reducing theseundesirable effects, such as use of chelating agents, would onlyfacilitate the oral swallowing and gastric absorption rather thanresulting in sublingual absorption.

It has also been demonstrated that riluzole is clinically relevant togeneralized anxiety disorder (GAD) and is useful for the attenuation ofpresynaptic glutamate release. Riluzole is also useful for thenormalization, enhancement or potentiation of the uptake of glutamate byglia (Coric et al. U.S. Pat. No. 8,778,979).

There is a long felt need for new treatments for melanoma that are bothdisease-modifying and effective in treating patients that are refractoryto current treatments. The present invention addresses the need toidentify new treatments for melanoma by identifying novel prodrugs ofriluzole which possess enhanced stability to hepatic metabolism and aredelivered into systemic circulation by oral administration. The presentinvention can also treat or prevent various neurological or CNS statesas well as depression/anxiety states. The riluzole prodrugs are cleavedto release riluzole in the plasma via either an enzymatic or generalbiophysical release process.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed toward riluzole derivatives of formula(I),

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof, wherein:R¹ is selected from the group consisting of C₁-C₆ fluoroalkyl, OR²,(CR^(6a)R^(6b))_(m)NHR⁷, CR^(10a)R^(10b)NR¹¹R¹²,

R² is selected from the group consisting of CH₂(CH₂)_(n)NR^(3a)R^(3b),

R^(3a) and R^(3b) are independently selected from the group consistingof hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, and CO₂R⁴;R^(3a) and R^(3b) cannot both be C₁-C₆ alkyl;R^(3a) and R^(3b) are taken together with the atom to which they arebound to form an optionally substituted three to six membered saturatedheterocyclic ring consisting of two to five carbon atoms and a memberselected from the group consisting of O, NR⁵, S, and SO₂;n is 1 or 2;R⁴ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₇ branchedalkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, optionallysubstituted phenyl, and optionally substituted benzyl;R⁵ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₇ branchedalkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;R^(6a) and R^(6b) are at each occurrence independently selected from thegroup consisting of hydrogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₃-C₇ branched alkyl, optionally substitutedC₃-C₇ cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;R^(6a) and R^(6b) are taken together with the atom to which they arebound to form an optionally substituted 6 membered ring;m is 1, 2, or 3;R⁷ is selected from the group consisting of COCR^(8a)R^(8b)(NHR⁹),

R^(8a) and R^(8b) are at each occurrence independently selected from thegroup consisting of hydrogen, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,CH₂OH, CH(OH)CH₃, CH₂Ph, CH₂(4-OH—Ph), (CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH,CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H, CH₂CH₂CO₂H, CH₂CONH₂, andCH₂CH₂CONH₂;R⁹ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;Y is at each occurrence independently selected from the group consistingof H₂ or O;R^(10a) and R^(10b) are at each occurrence independently selected fromthe group consisting of hydrogen, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂OH, CH₂OCH₂Ph, CH(OH)CH₃, CH₂Ph, CH₂(4-OH-Ph),(CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂(CCH),CH₂(cyclohexyl), CH₂CO₂H, CH₂CH₂CO₂H, CH₂CONH₂, and CH₂CH₂CONH₂;R^(10a) and R^(10b) are taken together with the atom to which they arebound to form an optionally substituted three to six membered saturatedcarbocyclic ring;R¹¹ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, and C₂-C₆ alkynyl;R^(10a) and R¹¹ are taken together with the atoms to which they arebound to form an optionally substituted four to six membered ringcontaining one nitrogen atom, and R¹² is not hydrogen;R^(10b) and R¹¹ are taken together with the atoms to which they arebound to form an optionally substituted four to six membered ringcontaining one nitrogen atom, and R¹² is not hydrogen;R¹² is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, COCR^(13a)R^(13b)NR^(15a)R^(15b),COCR^(13a)R^(13b)OR¹⁴, SO₂CR^(13a)R^(13b)NR^(15a)R^(15b),COCR^(13a)R^(13b)NHSO₂R^(15a),

and (CR^(19a)R^(19b))_(q)NHR²⁰, and when R¹² is hydrogen, R¹¹ cannot behydrogen;R¹¹ and R¹² are taken together with the atom to which they are bound toform an optionally substituted four to six membered saturatedheterocyclic ring containing a nitrogen atom and optionally containingan additional heteroatom from the group consisting of N and O;R^(13a) and R^(13b) are at each occurrence independently selected fromthe group consisting hydrogen, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH₂CCH, CH(CH₃)₂,CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂OH, CH₂OCH₂Ph, CH₂CH₂OCH₂Ph, CH(OH)CH₃,CH₂Ph, CH₂(cyclohexyl), CH₂(4-OH-Ph), (CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH,CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H, CH₂CH₂CO₂H, CH₂CONH₂, andCH₂CH₂CONH₂;R^(13a) and R^(13b) are taken together with the atom to which they arebound to form an optionally substituted three to six membered saturatedcarbocyclic ring;R^(13a) and R^(13b) are taken together with the atom to which they arebound to form an optionally substituted six membered saturatedheterocyclic ring with one O atom within the ring;R^(13a) and R¹⁴ are taken together with the atoms to which they arebound to form an optionally substituted four to six membered ringcontaining one nitrogen atom;R^(13a) and R^(15a) are taken together with the atoms to which they arebound to form an optionally substituted four to six membered ringcontaining one nitrogen atom;Y¹ is at each occurrence independently selected from the groupconsisting of H₂, O, and —H/—OCH₂Ph;R¹⁴ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;R^(15a) and R^(15b) are at each occurrence independently selected fromthe group consisting of H, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl C₁-C₆ fluoroalkyl, COR²¹,CH₂R²¹, SO₂R²², an optionally substituted four to six membered saturatedheterocyclic ring containing a heteroatom selected from the groupconsisting of NR²⁴ and O, COCHR²³NH₂,

R^(15a) and R^(15b) are taken together with the atom to which they arebound to form an optionally substituted three to six membered saturatedheterocyclic ring consisting of two to five carbon atoms and a memberselected from the group consisting of O, NR⁵, S, and SO₂;R¹⁶ is at each occurrence independently selected from the groupconsisting of CH₂, O, C═O, and NH;R¹⁷ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;R¹⁸ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;R¹⁷ and R¹⁸ are taken together with the atoms to which they are bound toform an optionally substituted five or six membered ring containing twonitrogen atoms;R^(19a) and R^(19b) are at each occurrence independently selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₃-C₇ branched alkyl, optionally substitutedC₃-C₇ cycloalkyl, optionally substituted C₂-C₆ alkenyl, and optionallysubstituted C₂-C₆ alkynyl;R^(19a) and R^(19b) are taken together with the atom to which they arebound to form an optionally substituted 3 to 6 membered carbocyclicring;R²⁰ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;q is 1, or 2;R²¹ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ fluoroalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl;R²² is at each occurrence independently selected from the groupconsisting of C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl;R²³ is selected from the group consisting H, CH₃, CH₂CH₃, CH₂CH₂CH₃,CH₂CCH, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂OH, CH₂OCH₂Ph,CH₂CH₂OCH₂Ph, CH(OH)CH₃, CH₂Ph, CH₂(cyclohexyl), CH₂(4-OH-Ph),(CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H,CH₂CH₂CO₂H, CH₂CONH₂, and CH₂CH₂CONH₂;R²⁴ is at each occurrence independently selected from the groupconsisting of H, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl, COR²⁵, and SO₂—C₁₋₆alkyl;R²⁵ is at each occurrence independently selected from the groupconsisting of H, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl, C₁-C₆ alkoxy, and C₁-C₆ alkylamino.

The compounds of the present invention include compounds having formula(II):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(III):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(IV):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(V):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(VI):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(VII):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(VIII):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(IX):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(X):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XI):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XII):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XIII):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XIV):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XV):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XVI):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XVII):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XVIII)

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof, wherein:R²³ is selected from the group consisting H, CH₃, CH₂CH₃, CH₂CH₂CH₃,CH₂CCH, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂OH, CH₂OCH₂Ph,CH₂CH₂OCH₂Ph, CH(OH)CH₃, CH₂Ph, CH₂(cyclohexyl), CH₂(4-OH-Ph),(CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H,CH₂CH₂CO₂H, CH₂CONH₂, and CH₂CH₂CONH₂.

The present invention further relates to compositions comprising:

an effective amount of one or more compounds according to the presentinvention and an excipient. The present invention yet further relates toan effective amount of one or more compounds according to the presentinvention and an anticancer agent.

The present invention also relates to a method for treating orpreventing cancer, particularly melanoma, said method comprisingadministering to a subject an effective amount of a compound orcomposition according to the present invention, possibly in conjunctionwith an excipient and/or an anticancer agent.

The present invention also relates to a method for treating orpreventing disease or conditions associated with cancer, particularlymelanoma. Said methods comprise administering to a subject an effectiveamount of a compound or composition according to the present invention,possibly in conjunction with an excipient and/or an anticancer agent.

Cancers that may be treated or prevented by administering to a subjectan effective amount of a compound or composition according to thepresent invention, or a pharmaceutically acceptable salt, solvate,anomer, enantiomer or hydrate thereof, possibly with an excipient or ananticancer agent, including ovarian cancer, cervical cancer, breastcancer, prostate cancer, testicular cancer, lung cancer, renal cancer,colorectal cancer, skin cancer, brain cancer including glioma andglioblastoma, and leukemia. The present invention also provides asublingual or sustained release formulation which may comprise aneffective amount of riluzole or a pharmaceutically acceptable salts,solvate, anomers, enantiomers, hydrate or prodrugs thereof to treatcancers in combination with immunotherapies (including alone or incombination with vaccines, anti-PD1, anti-PDL1, anti-CTLA4 or otherimmunotherapy or checkpoint inhibitor targets including: CTLA4,cytotoxic T-lymphocyte-associated antigen 4; Ig, immunoglobulin; LAG3,lymphocyte activation gene 3; mAbs, monoclonal antibodies; PD1,programmed cell death protein 1; PDL, PD1 ligand; TIM3, T cell membraneprotein 3, CD40L, A2aR, adenosine A2a receptor; B7RP1, B7-relatedprotein 1; BTLA, B and T lymphocyte attenuator; GALS, galectin 9; HVEM,herpesvirus entry mediator; ICOS, inducible T cell co-stimulator; IL,interleukin; KIR, killer cell immunoglobulin-like receptor; LAG3,lymphocyte activation gene 3; PD1, programmed cell

death protein 1; PDL, PD1 ligand; TGFβ, transforming growth factor-β;TIM3, T cell membrane protein 3; CD27).

The present invention also relates to a method for treating orpreventing various neurological or CNS states as well asdepression/anxiety states in which riluzole is clinically relevantincluding, but are not limited to, bipolar disorder, treatment resistantand major depression, general anxiety disorder, panic disorder, socialanxiety, mood disorders, cognitive disorders, dementia, agitation,apathy, psychoses, post-traumatic stress disorders, irritability,disinhibition, learning disorders, memory loss, personality disorders,bipolar disorders, Rett syndrome, eating disorders, conduct disorder,neurodegenerative disorders, pain disorders, supranuclear palsy,frontotemporal dementia, frontotemporal lobar degeneration, delirium,Alzheimer's disease, mild Alzheimer's disease, mild cognitiveimpairment, mild cognitive impairment due to Alzheimer's disease, drugaddiction, tinnitus, mental retardation, obsessive-compulsive disorder,spinal muscular atrophy, radiation therapy, multiple sclerosis, chroniccerebellar ataxia, hereditary spinocerebellar ataxia, spinocerebellarataxia, sporadic ataxia, episodic ataxia, Friedreich Ataxia, MultisystemAtrophy, ataxia associated with Anti-GAD antibodies target andonconeural antigen, essential tremor, cervical spondylotic myelopathy,spinal cord injury, hereditary cerebellar ataxia, Tourette syndrome,autism spectrum disorder, schizophrenia, fragile X syndrome, Parkinson'sDisease, Progressive Supranuclear Palsy, Dementia with Lewy Bodies, andHuntington's disease, said method comprising administering to a subjectan effective amount of a compound or composition according to thepresent invention, possibly with an excipient or other CNS drug such asserotonin reuptake inhibitor (SRI).

The present invention yet further relates to a method of enhancing theactivity of a serotonin reuptake inhibitor (SRI) in an individual inneed thereof. The methods comprise co-administering to the individual aneffective amount of a compound or composition according to the presentinvention and a SRI.

In certain embodiments, the serotonin reuptake inhibitor can becitalopram, escitalopram, flouxetine, fluvoxamine, paroxetine,sertraline, trazodone, venlafaxine, mirtazepine, clomipramine, orcombinations with other psychotropic medications including ananti-psychotic, an anticonvulsant, a tricyclic antidepressant, amonoamine oxidase inhibitor, a selective serotonin reuptake inhibitor, aselective serotonin-norepinephrine reuptake inhibitor, a norepinephrinedopamine reuptake inhibitor, a serotonin-2 antagonist reuptakeinhibitor, a benzodiazepine, a wakefulness promoting agent, anti-manicagent, or a combination of one or more of the foregoing. The presentinvention further relates to a process for preparing the riluzoleprodrugs of the present invention.

These and other objects, features, and advantages will become apparentto those of ordinary skill in the art from a reading of the followingdetailed description and the appended claims. All percentages, ratiosand proportions herein are by weight, unless otherwise specified. Alltemperatures are in degrees Celsius (° C.) unless otherwise specified.All documents cited are in relevant part, incorporated herein byreference; the citation of any document is not to be construed as anadmission that it is prior art with respect to the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Time concentration curve for example 125 and released riluzolevia both intravenous and oral administration.

FIG. 2: Melanoma (C8161) xenograft study in nude mice with example 125and riluzole given orally (RIL=Riluzole).

FIG. 3: Time-concentration curves for2-Amino-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}acetamide (Example 204)and released riluzole via both intravenous and oral administration.

FIG. 4: Melanoma (C8161) xenograft study in nude mice with example 204and riluzole given orally (RIL=Riluzole).

FIG. 5: PK in fasted male mice for Example 204, IV administration, 1mg/kg. and PO administration 5 mg/kg. Monitor disappearance of Prodrugand appearance of riluzole.

FIG. 6: PK in Cynomolgus Monkey for Example 204, IV administration, 1mg/kg. and PO administration 5 mg/kg. Monitor appearance of riluzole.

DETAILED DESCRIPTION OF THE INVENTION

The prodrugs of the present invention are capable of treating andpreventing cancers such as melanoma by releasing riluzole in vivo.Prodrugs of riluzole have enhanced stability to hepatic metabolism andare delivered into systemic circulation by oral administration, and arethen cleaved to release riluzole in the plasma via either an enzymaticor general biophysical release process. Riluzole has dramaticanti-melanoma activity in vitro, in mice and in a Phase 0 human clinicaltrial. The pro-drugs of the present invention are also capable oftreating and preventing other disease states in which riluzole isclinically relevant including, but are not limited to, amyotrophiclateral sclerosis (ALS) bipolar disorder, treatment resistant and majordepression, general anxiety disorder, panic disorder, social anxiety,mood disorders, cognitive disorders, dementia, agitation, apathy,psychoses, post-traumatic stress disorders, irritability, disinhibition,learning disorders, memory loss, personality disorders, bipolardisorders, Rett syndrome, eating disorders, conduct disorder,neurodegenerative disorders, pain disorders, supranuclear palsy,frontotemporal dementia, frontotemporal lobar degeneration, delirium,Alzheimer's disease, mild Alzheimer's disease, mild cognitiveimpairment, mild cognitive impairment due to Alzheimer's disease, drugaddiction, tinnitus, mental retardation, obsessive-compulsive disorder,spinal muscular atrophy, radiation therapy, multiple sclerosis, chroniccerebellar ataxia, hereditary spinocerebellar ataxia, spinocerebellarataxia, sporadic ataxia, episodic ataxia, Friedreich Ataxia, MultisystemAtrophy, ataxia associated with Anti-GAD antibodies target andonconeural antigen, essential tremor, cervical spondylotic myelopathy,spinal cord injury, hereditary cerebellar ataxia, Tourette syndrome,autism spectrum disorder, schizophrenia, fragile X syndrome, Parkinson'sDisease, Progressive Supranuclear Palsy, Dementia with Lewy Bodies, andHuntington's disease. Throughout the description, where compositions aredescribed as having, including, or comprising specific components, orwhere processes are described as having, including, or comprisingspecific process steps, it is contemplated that compositions of thepresent teachings also consist essentially of, or consist of, therecited components, and that the processes of the present teachings alsoconsist essentially of, or consist of, the recited processing steps.

In the application, where an element or component is said to be includedin and/or selected from a list of recited elements or components, itshould be understood that the element or component can be any one of therecited elements or components and can be selected from the groupconsisting of two or more of the recited elements or components.

The use of the singular herein includes the plural (and vice versa)unless specifically stated otherwise. In addition, where the use of theterm “about” is before a quantitative value, the present teachings alsoinclude the specific quantitative value itself, unless specificallystated otherwise.

It should be understood that the order of steps or order for performingcertain actions is immaterial so long as the present teachings remainoperable. Moreover, two or more steps or actions can be conductedsimultaneously

As used herein, the term “halogen” shall mean chlorine, bromine,fluorine and iodine.

As used herein, unless otherwise noted, “alkyl” and “aliphatic” whetherused alone or as part of a substituent group refers to straight andbranched carbon chains having 1 to 20 carbon atoms or any number withinthis range, for example 1 to 6 carbon atoms or 1 to 4 carbon atoms.Designated numbers of carbon atoms (e.g. C₁-C₆) shall referindependently to the number of carbon atoms in an alkyl moiety or to thealkyl portion of a larger alkyl-containing substituent. Non-limitingexamples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like. Alkyl groupscan be optionally substituted. Non-limiting examples of substitutedalkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl,aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl,3-carboxypropyl, and the like. In substituent groups with multiple alkylgroups such as (C₁-C₆ alkyl)₂amino, the alkyl groups may be the same ordifferent.

As used herein, “cycloalkyl,” whether used alone or as part of anothergroup, refers to a non-aromatic carbon-containing ring includingcyclized alkyl, alkenyl, and alkynyl groups, e.g., having from 3 to 14ring carbon atoms, preferably from 3 to 7 or 3 to 6 ring carbon atoms,or even 3 to 4 ring carbon atoms, and optionally containing one or more(e.g., 1, 2, or 3) double or triple bond. Cycloalkyl groups can bemonocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused,bridged, and/or spiro ring systems), wherein the carbon atoms arelocated inside or outside of the ring system. Any suitable ring positionof the cycloalkyl group can be covalently linked to the defined chemicalstructure. Cycloalkyl rings can be optionally substituted. Nonlimitingexamples of cycloalkyl groups include: cyclopropyl,2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl,2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl,decalinyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl,4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl,octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl,

decahydroazulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, anddodecahydro-1H-fluorenyl. The term “cycloalkyl” also includescarbocyclic rings which are bicyclic hydrocarbon rings, non-limitingexamples of which include, bicyclo-[2.1.1]hexanyl,bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl,1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, andbicyclo[3.3.3]undecanyl.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogen. Haloalkyl groupsinclude perhaloalkyl groups, wherein all hydrogens of an alkyl grouphave been replaced with halogens (e.g., —CF₃, CF₂CF₃). Haloalkyl groupscan optionally be substituted with one or more substituents in additionto halogen. Examples of haloalkyl groups include, but are not limitedto, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl,pentafluoroethyl, and pentachloroethyl groups.

The term “alkoxy” refers to the group O-alkyl, wherein the alkyl groupis as defined above. Alkoxy groups optionally may be substituted. Theterm v cyclic alkoxy refers to a ring containing 3 to 6 carbon atoms andat least one oxygen atom (e.g., tetrahydrofuran, tetrahydro-2H-pyran).C₃-C₆ cyclic alkoxy groups optionally may be substituted.

The term “aryl,” wherein used alone or as part of another group, isdefined herein as an unsaturated, aromatic monocyclic ring of 6 carbonmembers or to an unsaturated, aromatic polycyclic ring of from 10 to 14carbon members. Aryl rings can be, for example, phenyl or naphthyl ringeach optionally substituted with one or more moieties capable ofreplacing one or more hydrogen atoms. Non-limiting examples of arylgroups include: phenyl, naphthylen-1-yl, naphthylen-2-yl,4-fluorophenyl, 2-hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluorophenyl,2-(N,N-diethylamino)phenyl, 2-cyanophenyl, 2,6-di-tert-butylphenyl,3-methoxyphenyl, 8-hydroxynaphthylen-2-yl 4,5-dimethoxynaphthylen-1-yl,and 6-cyano-naphthylen-1-yl. Aryl groups also include, for example,phenyl or naphthyl rings fused with one or more saturated or partiallysaturated carbon rings (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl,indanyl), which can be substituted at one or more carbon atoms of thearomatic and/or saturated or partially saturated rings. The term“arylalkyl” or “aralkyl” refers to the group alkyl-aryl, where the alkyland aryl groups are as defined herein. Aralkyl groups of the presentinvention are optionally substituted.

Examples of arylalkyl groups include, for example, benzyl,1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl,fluorenylmethyl and the like.

The terms “heterocyclic” and/or “heterocycle” and/or “heterocyclyl,”whether used alone or as part of another group, are defined herein asone or more ring having from 3 to 20 atoms wherein at least one atom inat least one ring is a heteroatom selected from nitrogen (N), oxygen(O), or sulfur (S), and wherein further the ring that includes theheteroatom is non-aromatic. In heterocycle groups that include 2 or morefused rings, the non-heteroatom bearing ring may be aryl (e.g.,indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocyclegroups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatomsindependently selected from nitrogen (N), oxygen (O), or sulfur (S). Oneor more N or S atoms in a heterocycle group can be oxidized. Heterocyclegroups can be optionally substituted.

Non-limiting examples of heterocyclic units having a single ringinclude: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl,imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl,isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl,hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl,piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl(valerolactam), 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole,and 1,2,3,4-tetrahydro-quinoline. Non-limiting examples of heterocyclicunits having or more rings include: hexahydro-1H-pyrrolizinyl,3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl,3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl,chromanyl, isochromanyl, indolinyl, isoindolinyl, anddecahydro-1H-cycloocta[b]pyrrolyl.

The term “heteroaryl,” whether used alone or as part of another group,is defined herein as one or more rings having from 5 to 20 atoms whereinat least one atom in at least one ring is a heteroatom chosen fromnitrogen (N), oxygen (O), or sulfur (S), and wherein further at leastone of the rings that includes a heteroatom is aromatic. In heteroarylgroups that include 2 or more fused rings, the non-heteroatom bearingring may be a carbocycle (e.g., 6,7-Dihydro-5H-cyclopentapyrimidine) oraryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplaryheteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5ring heteroatoms independently selected from nitrogen (N), oxygen (O),or sulfur (S). One or more N or S atoms in a heteroaryl group can beoxidized. Heteroaryl groups can be substituted. Non-limiting examples ofheteroaryl rings containing a single ring include: 1,2,3,4-tetrazolyl,[1,2,3]triazolyl,

[1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl,furanyl, thiopheneyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl,3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limiting examplesof heteroaryl rings containing 2 or more fused rings include:benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl,9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl,7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl,benzo[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl,quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl,8-hydroxy-quinolinyl, and isoquinolinyl.

Unless otherwise noted, when two substituents are taken together to forma ring having a specified number of ring atoms (e.g., R² and R³ takentogether with the nitrogen (N) to which they are attached to form a ringhaving from 3 to 7 ring members), the ring can have carbon atoms andoptionally one or more (e.g., 1 to 3) additional heteroatomsindependently selected from nitrogen (N), oxygen (O), or sulfur (S). Thering can be saturated or partially saturated and can be optionallysubstituted. For the purposed of the present invention fused ring units,as well as spirocyclic rings, bicyclic rings and the like, whichcomprise a single heteroatom will be considered to belong to the cyclicfamily corresponding to the heteroatom containing ring. For example,1,2,3,4-tetrahydroquinoline having the formula:

is, for the purposes of the present invention, considered a heterocyclicunit. 6,7-Dihydro-5H-cyclopentapyrimidine having the formula:

is, for the purposes of the present invention, considered a heteroarylunit. When a fused ring unit contains heteroatoms in both a saturatedand an aryl ring, the aryl ring will predominate and determine the typeof category to which the ring is assigned. For example,1,2,3,4-tetrahydro-[1,8]naphthyridine having the formula:

is, for the purposes of the present invention, considered a heteroarylunit.

Whenever a term or either of their prefix roots appear in a name of asubstituent the name is to be interpreted as including those limitationsprovided herein. For example, whenever the term “alkyl” or “aryl” oreither of their prefix roots appear in a name of a substituent (e.g.,arylalkyl, alkylamino) the name is to be interpreted as including thoselimitations given above for “alkyl” and “aryl.”

The term “substituted” is used throughout the specification. The term“substituted” is defined herein as a moiety, whether acyclic or cyclic,which has one or more hydrogen atoms replaced by a substituent orseveral (e.g., 1 to 10) substituents as defined herein below. Thesubstituents are capable of replacing one or two hydrogen atoms of asingle moiety at a time. In addition, these substituents can replace twohydrogen atoms on two adjacent carbons to form said substituent, newmoiety or unit. For example, a substituted unit that requires a singlehydrogen atom replacement includes halogen, hydroxyl, and the like. Atwo hydrogen atom replacement includes carbonyl, oximino, and the like.A two hydrogen atom replacement from adjacent carbon atoms includesepoxy, and the like. The term “substituted” is used throughout thepresent specification to indicate that a moiety can have one or more ofthe hydrogen atoms replaced by a substituent. When a moiety is describedas “substituted” any number of the hydrogen atoms may be replaced. Forexample, difluoromethyl is a substituted C₁ alkyl; trifluoromethyl is asubstituted C₁ alkyl; 4-hydroxyphenyl is a substituted aromatic ring;(N,N-dimethyl-5-amino)octanyl is a substituted C₈ alkyl;3-guanidinopropyl is a substituted C₃ alkyl; and 2-carboxypyridinyl is asubstituted heteroaryl.

The variable groups defined herein, e.g., alkyl, cycloalkyl, alkoxy,aryloxy, aryl, heterocycle and heteroaryl groups defined herein, whetherused alone or as part of another group, can be optionally substituted.Optionally substituted groups will be so indicated.

The following are non-limiting examples of substituents which cansubstitute for hydrogen atoms on a moiety: halogen (chlorine (Cl),bromine (Br), fluorine (F) and iodine (I)), —CN, —NO₂, oxo (═O), —OR²⁶,—SR²⁶, —N(R²⁶)₂, —NR²⁶C(O)R²⁶, —SO₂R²⁶, —SO₂OR²⁶, —SO₂N(R²⁶)₂, —C(O)R²⁶,—C(O)OR²⁶, —C(O)N(R²⁶)₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₁₄ cycloalkyl, aryl, heterocycle, orheteroaryl, wherein each of the alkyl, haloalkyl, alkenyl, alkynyl,alkoxy, cycloalkyl, aryl, heterocycle, and heteroaryl groups isoptionally substituted with 1-10 (e.g., 1-6 or 1-4) groups selectedindependently from halogen, —CN, —NO₂, oxo, and R²⁶; wherein R²⁶, ateach occurrence, independently is hydrogen, —OR²⁷, —SR²⁷, —C(O)R²⁷,—C(O)OR²⁷, —C(O)N(R²⁷)₂, —SO₂R²⁷, —S(O)₂OR²⁷, —N(R²⁷)₂, —N(R²⁷)₂,—NR²⁷C(O)R²⁷, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,cycloalkyl (e.g., C₃₋₆ cycloalkyl), aryl, heterocycle, or heteroaryl, ortwo R²⁶ units taken together with the atom(s) to which they are boundform an optionally substituted carbocycle or heterocycle wherein saidcarbocycle or heterocycle has 3 to 7 ring atoms; wherein R²⁷, at eachoccurrence, independently is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, cycloalkyl (e.g., C₃₋₆ cycloalkyl), aryl,heterocycle, or heteroaryl, or two R²⁷ units taken together with theatom(s) to which they are bound form an optionally substitutedcarbocycle or heterocycle wherein said carbocycle or heterocyclepreferably has 3 to 7 ring atoms.

In some embodiments, the substituents are selected from

-   -   i) OR²⁸; for example, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃;    -   ii) —C(O)R²⁸; for example, —COCH₃, —COCH₂CH₃, —COCH₂CH₂CH₃;    -   iii) —C(O)OR²⁸; for example, —CO₂CH₃, —CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃;    -   iv) —C(O)N(R²⁸)₂; for example, —CONH₂, —CONHCH₃, —CON(CH₃)₂;    -   v) —N(R²⁸)₂; for example, —NH₂, —NHCH₃, —N(CH₃)₂, —NH(CH₂CH₃);    -   vi) halogen: —F, —Cl, —Br, and —I;    -   vii) —CH_(e)X_(g); wherein X is halogen, m is from 0 to 2,        e+g=3; for example, —CH₂F, —CHF₂, —CF₃, —CCl₃, or —CBr₃;    -   viii) —SO₂R²⁸; for example, —SO₂H; —SO₂CH₃; —SO₂C₆H₅;    -   ix) C₁-C₆ linear, branched, or cyclic alkyl;    -   x) Cyano    -   xi) Nitro;    -   xii) N(R²⁸)C(O)R²⁸;    -   xiii) Oxo (═O);    -   xiv) Heterocycle; and    -   xv) Heteroaryl.    -   wherein each R²⁸ is independently hydrogen, optionally        substituted C₁-C₆ linear or branched alkyl (e.g., optionally        substituted C₁-C₄ linear or branched alkyl), or optionally        substituted C₃-C₆ cycloalkyl (e.g optionally substituted C₃-C₄        cycloalkyl); or two R²⁸ units can be taken together to form a        ring comprising 3-7 ring atoms. In certain aspects, each R²⁸ is        independently hydrogen, C₁-C₆ linear or branched alkyl        optionally substituted with halogen or C₃-C₆ cycloalkyl or C₃-C₆        cycloalkyl.

At various places in the present specification, substituents ofcompounds are disclosed in groups or in ranges. It is specificallyintended that the description include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁-C₆ alkyl” is specifically intended to individually discloseC₁, C₂, C₃, C₄, C₅, C₆, C₁-C₆, C₁-C₅, C₁-C₄, C₁-C₃, C₁-C₂, C₂-C₆, C₂-C₅,C₂-C₄, C₂-C₃, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₆, C₄-C₅, and C₅-C₆, alkyl.

For the purposes of the present invention the terms “compound,”“analog,” and “composition of matter” stand equally well for the prodrugagent described herein, including all enantiomeric forms, diastereomericforms, salts, and the like, and the terms “compound,” “analog,” and“composition of matter” are used interchangeably throughout the presentspecification.

Compounds described herein can contain an asymmetric atom (also referredas a chiral center), and some of the compounds can contain one or moreasymmetric atoms or centers, which can thus give rise to optical isomers(enantiomers) and diastereomers. The present teachings and compoundsdisclosed herein include such enantiomers and diastereomers, as well asthe racemic and resolved, enantiomerically pure R and S stereoisomers,as well as other mixtures of the R and S stereoisomers andpharmaceutically acceptable salts thereof. Optical isomers can beobtained in pure form by standard procedures known to those skilled inthe art, which include, but are not limited to, diastereomeric saltformation, kinetic resolution, and asymmetric synthesis. The presentteachings also encompass cis and trans isomers of compounds containingalkenyl moieties (e.g., alkenes and imines). It is also understood thatthe present teachings encompass all possible regioisomers, and mixturesthereof, which can be obtained in pure form by standard separationprocedures known to those skilled in the art, and include, but are notlimited to, column chromatography, thin-layer chromatography, andhigh-performance liquid chromatography.

Pharmaceutically acceptable salts of compounds of the present teachings,which can have an acidic moiety, can be formed using organic andinorganic bases. Both mono and polyanionic salts are contemplated,depending on the number of acidic hydrogens available for deprotonation.Suitable salts formed with bases include metal salts, such as alkalimetal or alkaline earth metal salts, for example sodium, potassium, ormagnesium salts; ammonia salts and organic amine salts, such as thoseformed with morpholine, thiomorpholine, piperidine, pyrrolidine, amono-, di- or tri-lower alkylamine (e.g., ethyl-tert-butyl-, diethyl-,diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-,di-, or trihydroxy lower alkylamine (e.g., mono-, di- ortriethanolamine). Specific non-limiting examples of inorganic basesinclude NaHCO₃, Na₂CO₃, KHCO₃, K₂CO₃, Cs₂CO₃, LiOH, NaOH, KOH, NaH₂PO₄,Na₂HPO₄, and Na₃PO₄. Internal salts also can be formed. Similarly, whena compound disclosed herein contains a basic moiety, salts can be formedusing organic and inorganic acids. For example, salts can be formed fromthe following acids: acetic, propionic, lactic, benzenesulfonic,benzoic, camphorsulfonic, citric, tartaric, succinic, dichloroacetic,ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic,mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic,pamoic, pantothenic, phosphoric, phthalic, propionic, succinic,sulfuric, tartaric, toluenesulfonic, and camphorsulfonic as well asother known pharmaceutically acceptable acids.

When any variable occurs more than one time in any constituent or in anyformula, its definition in each occurrence is independent of itsdefinition at every other occurrence (e.g., in N(R¹³)₂, each R³ may bethe same or different than the other). Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

The term “neuropsychiatric disorder”, as used herein, is a mental orneurologic disorder which is associated with the nervous system. Forexample, the neuropsychiatric disorder may include anxiety disorders,mood disorders, neurodegenerative disorders, neurodevelopmentaldisorders, autism, pervasive developmental disorder, pain disorders,neuropathic pain, ALS, cognitive disorders, Huntington's disease,Parkinson's disease, supranuclear palsy, frontal temporal dementia,schizophrenia, delirium, Alzheimer's disease including mild Alzheimer'sdisease, depression, mania, attention deficit disorders, drug addiction,dementia, agitation, apathy, anxiety, psychoses, post-traumatic stressdisorders, irritability, and disinhibition, learning disorders, memoryloss, mental retardation, dementia, personality disorders, bipolardisorders, bipolar depression, generalized anxiety

disorder, panic disorder, obsessive-compulsive disorders,trichotillomania, eating disorders, and the like. More specifically,neuropsychiatric disorders includes those listed in the Diagnostic andStatistical Manual of Mental Disorders (American PsychiatricAssociation, 5th Edition): Neurodevelopmental disorders, Intellectualdisabilities, Intellectual disability (intellectual developmentaldisorder), Global developmental delay, Unspecified intellectualdisability (Intellectual developmental disorder), Communicationdisorders, Language disorder, Speech sound disorder, Childhood-onsetfluency disorder (stuttering), Social (pragmatic) communicationdisorder, Unspecified communication disorder, Autism spectrum disorder,Rett Syndrome, Attention deficit hyperactivity disorder (ADHD),Unspecified attention-deficit/Hyperactivity disorder, Specific learningdisorder, Motor disorders, Developmental coordination disorder,Stereotypic movement disorder, Tic disorders, Tourette's disorder,Persistent (Chronic) motor or vocal tic disorder, Provisional ticdisorder, Other specified tic disorder, Unspecified tic disorder, Otherneurodevelopmental disorders, Unspecified neurodevelopmental disorder,Schizophrenia spectrum and other psychotic disorders, Delusionaldisorder, Brief psychotic disorder, Schizophreniform disorder,Schizophrenia, Schizoaffective disorder, Major depressive or manic mooddisorder concurrent with primary symptoms of schizophrenia,Substance/Medication-induced psychotic disorder, Psychotic disorder dueto another medical condition, Catatonia, Other specified schizophreniaspectrum and other psychotic disorder, Unspecified schizophreniaspectrum and other psychotic disorder, Bipolar and related disorders,Anxiety disorders, Obsessive-compulsive and related disorders, Trauma-and stressor-related disorders, Reactive attachment disorder,Disinhibited social engagement disorder, Posttraumatic stress disorder,Acute stress disorder, Adjustment disorder, Other specified Trauma- andstressor-related disorder, Unspecified trauma- and stressor-relateddisorder, Dissociative disorders, Dissociative identity disorder,Dissociative amnesia, Depersonalization/Derealization disorder, Somaticsymptom disorders, Encopresis, other elimination disorder, Disruptive,impulse-control and conduct disorders in DSM-5, Oppositional defiantdisorder, Intermittent explosive disorder, Conduct disorder, Otherspecified disruptive, conduct disorder, unspecified disruptive, andconduct disorder, Substance-Related and Addictive Disorders,Substance-Related Disorders, Alcohol-Related Disorders, Alcohol UseDisorder, Alcohol Withdrawal, Cannabis-Related Disorders, Cannabis UseDisorder, Gambling Disorder, Cluster A personality disorders, Paranoidpersonalitydisorder, Schizoid personality disorder, Schizotypal personalitydisorder, Cluster B personality disorders, Antisocial personalitydisorder, Borderline personality disorder, Histrionic personalitydisorder, Narcissistic personality disorder, Cluster C personalitydisorders, Avoidant personality disorder, Dependent personalitydisorder, Obsessive-compulsive personality disorder, Paraphilicdisorders.

The term “DSM” refers to a Diagnostic and Statistical Manual of MentalDisorders as provided by American Psychiatric Association's (APA)classification and diagnostic tool. Diagnostic and Statistical Manual ofMental Disorders, Fifth Edition (DSM-5 or DSM-V) is updated in 2013 andexemplary disorders in DSM-V are listed in Appendix A. In addition, theDSM-V has a structure that includes broad categories and subdiagnosesindicating disorders, conditions and problems.

“Neuropsychiatric disorders” could also include neurodegenerative orneurologic disorders including: Alzheimer's disease, dementia, vasculardementia, mixed dementia, Parkinson's disease, Huntington's disease,Amyotrophic lateral sclerosis (ALS), pseudobulbar affect, agitation inAlzheimer's disease including mild Alzheimer's disease, dementia,cerebellar ataxia, hereditary ataxias, multiple sclerosis, ProgressiveSupranuclear Palsy, pain disorders, neuropathic pain, neuropathies,stroke, seizure, Fragile X, etc.

The neuropsychiatric symptoms may include anxiety, depression, stress,fatigue, feelings of panic, fear, uneasiness, problems in sleeping, coldor sweaty hands and/or feet, shortness of breath, heart palpitations,social phobia, fear of public speaking, an inability to be still andcalm, dry mouth, numbness or tingling in the hands or feet, nausea,muscle tension, dizziness apathy, elation, disinhibition, irritability,wandering, and the like. Additionally, neuropsychiatric symptoms couldinclude: delusions, hallucinations, disorganized thinking or speech,derailment of focal topic or loose associations, incoherence, grosslydisorganized or abnormal motor behavior (including catatonia), negativesymptoms—reduced emotional expression, avolition, alogia, anhedonia,asociality, dyskinesias (including tardive dyskinesia), anhedonia anddysphoria, anger and aggression, or symptoms of dissociation, or somecombination of these.

In an embodiment, provided is a method of treating mild Alzheimer'sDisease in a patient in need thereof, which includes administering tothe patient a therapeutically effective amount of a riluzole prodrug.Mild Alzheimer's Disease is an early stage Alzheimer's Disease, where aperson may still function independently. She or he may drive, work andbe part of social activities. Despite this, the person may feel as ifshe or he is having memory lapses, such as forgetting familiar words orthe location of everyday objects. Symptoms may not be widely apparent atthis stage, but family and close friends may take notice and a doctorwould be able to identify symptoms using certain diagnostic tools.Common difficulties may include coming up with the right word or name,remembering names when introduced to new people, having difficultyperforming tasks in social or work settings, forgetting material thatwas just read, losing or misplacing a valuable object, and experiencingincreased trouble with planning or organizing. More information aboutthe stages of Alzheimer's Disease may found athttps://www.alz.org/alzheimers-dementia/stages.

Other disorders treated could include cancer (including AcuteLymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML),Adrenocortical Carcinoms, Childhood cancers, AIDS-Related Cancers,Kaposi Sarcoma, AIDS-Related Lymphoma, Primary CNS Lymphoma, AnalCancer, Astrocytomas, Atypical Teratoid/Rhabdoid Tumor, Basal CellCarcinoma, Skin Cancer (Nonmelanoma), Bile Duct Cancer, Bladder Cancer,Bone Cancer, Ewing Sarcoma Family of Tumors, Osteosarcoma and MalignantFibrous Histiocytoma, Brain Stem Glioma, Atypical Teratoid/RhabdoidTumor, Embryonal Tumors, Germ Cell Tumors, Craniopharyngioma,Ependymoma, Breast Cancer, Bronchial Tumors, Burkitt Lymphoma,Non-Hodgkin Lymphoma, Carcinoid Tumor, Gastrointestinal Carcinoma,Cardiac (Heart) Tumors, Primary Lymphoma, Cervical Cancer,Cholangiocarcinoma, Chordoma, Chronic Lymphocytic Leukemia (CLL),Chronic Myelogenous Leukemia (CML), Chronic MyeloproliferativeNeoplasms, Colon Cancer, Colorectal Cancer, Craniopharyngioma, CutaneousT-Cell Lymphoma, Mycosis Fungoides and Sézary Syndrome, Ductal CarcinomaIn Situ (DCIS), Embryonal Tumors, Endometrial Cancer, Ependymoma,Esophageal Cancer, Esthesioneuroblastoma, Extracranial Germ Cell Tumor,Extragonadal Germ Cell Tumor, Eye Cancer, Intraocular Melanoma,Retinoblastoma, Fallopian Tube Cancer, Fibrous Histiocytoma of Bone,Malignant, and Osteosarcoma, Gallbladder Cancer, Gastric (Stomach)Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal StromalTumors (GIST), Germ Cell Tumor, Ovarian, Testicular, GestationalTrophoblastic Disease, Glioma, Hairy Cell Leukemia, Head and NeckCancer, Hepatocellular (Liver) Cancer, Histiocytosis, Langerhans Cell,Hodgkin Lymphoma, Hypopharyngeal Cancer, Islet Cell Tumors, PancreaticNeuroendocrine Tumors, Kaposi Sarcoma, Kidney, Renal Cell, Wilms Tumor,Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia, AcuteLymphoblastic (ALL), Acute Myeloid (AML), Chronic Lymphocytic (CLL),Chronic Myelogenous (CML), Hairy Cell, Lip and Oral Cavity Cancer, LiverCancer (Primary), Lung Cancer, Non-Small Cell, Small Cell, Lymphoma,Hodgkin, Non-Hodgkin, Macroglobulinemia, Waldenström, Male BreastCancer, Melanoma, Merkel Cell Carcinoma, Mesothelioma, MetastaticSquamous Neck Cancer with Occult Primary, Midline Tract CarcinomaInvolving NUT Gene, Mouth Cancer, Multiple Endocrine NeoplasiaSyndromes, Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides,Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms,Myelogenous Leukemia, Chronic (CML), Myeloid Leukemia, Acute (AML)Myeloma, Multiple, Myeloproliferative Neoplasms, Nasal Cavity andParanasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma,Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, OralCavity Cancer, Lip and Oropharyngeal Cancer, Osteosarcoma and MalignantFibrous Histiocytoma of Bone, Ovarian Cancer, Low Malignant PotentialTumor, Pancreatic Cancer, Pancreatic Neuroendocrine Tumors (Islet CellTumors), Papillomatosis, Paraganglioma, Paranasal Sinus and Nasal CavityCancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer,Pheochromocytoma, Pituitary Tumor, Plasma Cell Neoplasm/MultipleMyeloma, Pleuropulmonary Blastoma, Pregnancy and Breast Cancer, PrimaryCentral Nervous System (CNS) Lymphoma, Primary Peritoneal Cancer,Prostate Cancer, Rectal Cancer, Renal Cell (Kidney) Cancer, Renal Pelvisand Ureter, Transitional Cell Cancer, Retinoblastoma, Rhabdomyosarcoma,Salivary Gland Cancer, Rhabdomyosarcoma, Uterine, Small IntestineCancer, Soft Tissue Sarcoma, Sqamous Cell Carcinoma, Squamous NeckCancer with Occult Primary, Metastatic, Ttomach (Gastric) Cancer, T-CellLymphoma, Testicular Cancer, Throat Cancer, Thymoma and ThymicCarcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvisand Ureter, Unknown Primary, Ureter and Renal Pelvis, Transitional CellCancer, Urethral Cancer, Uterine Cancer, Endometrial, Uterine Sarcoma,Vaginal Cancer, Vulvar Cancer, Waldenstrom Macroglobulinemia, WilmsTumor.

The term “treatment” as used herein includes any treatment of acondition or disease in a subject, or particularly a human, and mayinclude: (i) preventing the disease or condition from occurring in thesubject which may be predisposed to the disease but has not yet beendiagnosed as having it; (ii) inhibiting the disease or condition, i.e.,arresting its development; relieving the disease or condition, i.e.,causing regression of the condition; or (iii) ameliorating or relievingthe conditions caused by the disease, i.e., symptoms of the disease.“Treatment” could be in combination with other standard therapies oralone.

As used herein, “therapeutically effective” and “effective dose” referto a substance or an amount that elicits a desirable biological activityor effect.

As used herein, the term “riluzole prodrug” shall mean a compound thatare cleaved to release riluzole in the plasma via either an enzymatic orgeneral biophysical release process.

As used herein, the term “prodrug agent” shall mean a compound that arecleaved to release riluzole in the plasma via either an enzymatic orgeneral biophysical release process.

As used herein, the term “anticancer agent” shall mean a compound thatis useful for the treatment or prevention of cancer, including but notlimited to melanoma, ovarian cancer, cervical cancer, breast cancer,prostate cancer, testicular cancer, lung cancer, renal cancer,colorectal cancer, skin cancer, brain cancer, and leukemia.

Except when noted, the terms “subject” or “patient” are usedinterchangeably and refer to mammals such as human patients andnon-human primates, as well as experimental animals such as rabbits,rats, and mice, and other animals. Accordingly, the term “subject” or“patient” as used herein means any mammalian patient or subject to whichthe compounds of the invention can be administered. In an exemplaryembodiment of the present invention, to identify subject patients fortreatment according to the methods of the invention, accepted screeningmethods are employed to determine risk factors associated with atargeted or suspected disease or condition or to determine the status ofan existing disease or condition in a subject. These screening methodsinclude, for example, conventional work-ups to determine risk factorsthat may be associated with the targeted or suspected disease orcondition. These and other routine methods allow the clinician to selectpatients in need of therapy using the methods and compounds of thepresent invention.

The Prodrug Agents:

The prodrug agents of the present invention are N-substituted riluzoleanalogs, and include all enantiomeric and diastereomeric forms andpharmaceutically accepted salts thereof having the formula (I):

including hydrates, solvates, pharmaceutically acceptable salts, andcomplexes thereof, wherein: R¹ is selected from the group consisting ofC₁-C₆ fluoroalkyl, OR², (CR^(6a)R^(6b))_(m)NHR⁷, CR^(10a)R^(10b)NR¹¹R¹²,

R² is selected from the group consisting of CH₂(CH₂)_(n)NR^(3a)R^(3b),

R^(3a) and R^(3b) are independently selected from the group consistingof hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, and CO₂R⁴;R^(3a) and R^(3b) cannot both be C₁-C₆ alkyl;R^(3a) and R^(3b) are taken together with the atom to which they arebound to form an optionally substituted three to six membered saturatedheterocyclic ring consisting of two to five carbon atoms and a memberselected from the group consisting of O, NR⁵, S, and SO₂;n is 1 or 2;R⁴ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₇ branchedalkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, optionallysubstituted phenyl, and optionally substituted benzyl;R⁵ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₇ branchedalkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;R^(6a) and R^(6b) are at each occurrence independently selected from thegroup consisting of hydrogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₃-C₇ branched alkyl, optionally substitutedC₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl, and optionallysubstituted C₃-C₇ cycloalkyl;R^(6a) and R^(6b) are taken together with the atom to which they arebound to form an optionally substituted 6 membered ring;m is 1, 2, or 3;R⁷ is selected from the group consisting of COC R^(8a)R^(8b)(NHR⁹);

R^(8a) and R^(8b) are at each occurrence independently selected from thegroup consisting of hydrogen, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,CH₂OH, CH(OH)CH₃, CH₂Ph, CH₂(4-OH-Ph), (CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH,CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H, CH₂CH₂CO₂H, CH₂CONH₂, andCH₂CH₂CONH₂;R⁹ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;Y is at each occurrence independently selected from the group consistingof H₂ or O;R^(10a) and R^(10b) are at each occurrence independently selected fromthe group consisting of hydrogen, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂OH, CH₂OCH₂Ph, CH(OH)CH₃, CH₂Ph, CH₂(4-OH-Ph),(CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂(CCH),CH₂(cyclohexyl), CH₂CO₂H, CH₂CH₂CO₂H, CH₂CONH₂, and CH₂CH₂CONH₂;R^(10a) and R^(10b) are taken together with the atom to which they arebound to form an optionally substituted three to six membered saturatedcarbocyclic ring;R¹¹ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, and C₂-C₆ alkynyl;R^(10a) and R¹¹ are taken together with the atoms to which they arebound to form an optionally substituted four to six membered ringcontaining one nitrogen atom, and R¹² is not hydrogen;R^(10b) and R¹¹ are taken together with the atoms to which they arebound to form an optionally substituted four to six membered ringcontaining one nitrogen atom, and R¹² is not hydrogen;R¹² is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, COCR^(13a)R^(13b)NR^(15a)R^(15b),COCR^(13a)R^(13b)OR¹⁴, SO₂CR^(13a)R^(13b)NR^(15a)R^(15b),COCR^(13a)R^(13b)NHSO₂R^(15a),

and (CR^(19a)R^(19b)) and (CR^(19a)R^(19b))_(q)NHR²⁰, and when R¹² ishydrogen, R¹¹ cannot be hydrogen;R¹¹ and R¹² are taken together with the atom to which they are bound toform an optionally substituted four to six membered saturatedheterocyclic ring containing a nitrogen atom and optionally containingan additional heteroatom from the group consisting of N and O;R^(13a) and R^(13b) are at each occurrence independently selected fromthe group consisting hydrogen, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH₂CCH, CH(CH₃)₂,CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂OH, CH₂OCH₂Ph, CH₂CH₂OCH₂Ph, CH(OH)CH₃,CH₂Ph, CH₂(cyclohexyl), CH₂(4-OH-Ph), (CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH,CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H, CH₂CH₂CO₂H, CH₂CONH₂, andCH₂CH₂CONH₂;R^(13a) and R^(13b) are taken together with the atom to which they arebound to form an optionally substituted three to six membered saturatedcarbocyclic ring;R^(13a) and R^(13b) are taken together with the atom to which they arebound to form an optionally substituted six membered saturatedheterocyclic ring with one O atom within the ring;R^(13a) and R¹⁴ are taken together with the atoms to which they arebound to form an optionally substituted four to six membered ringcontaining one nitrogen atom;R^(13a) and R^(15a) are taken together with the atoms to which they arebound to form an optionally substituted four to six membered ringcontaining one nitrogen atom;Y¹ is at each occurrence independently selected from the groupconsisting of H₂, O, and —H/—OCH₂Ph;R¹⁴ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;R^(15a) and R^(15b) are at each occurrence independently selected fromthe group consisting of H, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ fluoroalkyl, COR²¹,CH₂R²¹, SO₂R²², an optionally substituted four to six membered saturatedheterocyclic ring containing a heteroatom selected from the groupconsisting of NR²⁴ and O, COCHR²³NH₂,

R^(15a) and R^(15b) are taken together with the atom to which they arebound to form an optionally substituted four to six membered saturatedheterocyclic ring optionally containing one O atom within the ring;R¹⁶ is at each occurrence independently selected from the groupconsisting of CH₂, O, C═O, and

NH;

R¹⁷ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;R¹⁸ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;R¹⁷ and R¹⁸ are taken together with the atoms to which they are bound toform an optionally substituted five or six membered ring containing twonitrogen atoms;R^(19a) and R^(19b) are at each occurrence independently selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₃-C₇ branched alkyl, optionally substitutedC₃-C₇ cycloalkyl, optionally substituted C₂-C₆ alkenyl, and optionallysubstituted C₂-C₆ alkynyl;R^(19a) and R^(19b) are taken together with the atom to which they arebound to form an optionally substituted 3 to 6 membered carbocyclicring;R²⁰ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;q is 1, or 2;R²¹ is at each occurrence independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ fluoroalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl;R²² is at each occurrence independently selected from the groupconsisting of C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl optionally substituted aryl, optionallysubstituted heteroaryl;R²³ is selected from the group consisting H, CH₃, CH₂CH₃, CH₂CH₂CH₃,CH₂CCH, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂OH, CH₂OCH₂Ph,CH₂CH₂OCH₂Ph, CH(OH)CH₃, CH₂Ph, CH₂(cyclohexyl), CH₂(4-OH-Ph),(CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H,CH₂CH₂CO₂H, CH₂CONH₂, and CH₂CH₂CONH₂;R²⁴ is at each occurrence independently selected from the groupconsisting of H, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl, COR²⁵, and SO₂—C₁₋₆ alkyl;R²⁵ is at each occurrence independently selected from the groupconsisting of H, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl, C₁-C₆alkoxy, and C₁-C₆ alkylamino.

The compounds of the present invention include compounds having formula(II):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(III):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(IV):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(V):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(VI):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(VII):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(VIII):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(IX):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(X):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XI):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XII):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XIII):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XIV):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XV):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XVI):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XVII):

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula(XVIII)

including enantiomers, diastereomers, hydrates, solvates,pharmaceutically acceptable salts, and complexes thereof, wherein:R²³ is selected from the group consisting H, CH₃, CH₂CH₃, CH₂CH₂CH₃,CH₂CCH, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂OH, CH₂OCH₂Ph,CH₂CH₂OCH₂Ph, CH(OH)CH₃, CH₂Ph, CH₂(cyclohexyl), CH₂(4-OH-Ph),(CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H,CH₂CH₂CO₂H, CH₂CONH₂, and CH₂CH₂CONH₂.

In some embodiments R¹ is C₁-C₆ fluoroalkyl.

In some embodiments R¹ is OR².

In some embodiments R¹ is (CR^(6a)R^(6b))_(m)NHR⁷.

In some embodiments R¹ is CR^(10a)R^(10b)NR¹¹R¹².

In some embodiments R¹ is

In some embodiments R¹ is

In some embodiments R¹ is

In some embodiments R² is CH₂(CH₂)_(n)NR^(3a)R^(3b).

In some embodiments R² is

In some embodiments R^(3a) is hydrogen.

In some embodiments R^(3a) is C₁-C₆ alkyl.

In some embodiments R^(3a) is C₃-C₇ cycloalkyl.

In some embodiments R^(3a) is C₃-C₇ branched alkyl.

In some embodiments R^(3a) is C₂-C₆ alkenyl.

In some embodiments R^(3a) is C₂-C₆ alkynyl.

In some embodiments R^(3a) is CO₂R⁴.

In some embodiments R^(3b) is hydrogen.

In some embodiments R^(3b) is C₁-C₆ alkyl.

In some embodiments R^(3b) is C₃-C₇ cycloalkyl.

In some embodiments R^(3b) is C₃-C₇ branched alkyl.

In some embodiments R^(3b) is C₂-C₆ alkenyl.

In some embodiments R^(3b) is C₂-C₆ alkynyl.

In some embodiments R^(3b) is CO₂R⁴.

In some embodiments R^(3a) and R^(3b) are taken together with the atomto which they are bound to form an optionally substituted three to sixmembered saturated heterocyclic ring consisting of two to five carbonatoms and a member selected from the group consisting of O, NR⁵, S, andSO₂;

In some embodiments n is 1.

In some embodiments n is 2.

In some embodiments R⁴ is C₁-C₆ alkyl.

In some embodiments R⁴ is C₃-C₇ branched alkyl.

In some embodiments R⁴ is C₃-C₇ cycloalkyl.

In some embodiments R⁴ is C₂-C₆ alkenyl.

In some embodiments R⁴ is C₂-C₆ alkynyl.

In some embodiments R⁴ is optionally substituted phenyl.

In some embodiments R⁴ is benzyl.

In some embodiments R⁵ is C₁-C₆ alkyl

In some embodiments R⁵ is C₃-C₇ branched alkyl

In some embodiments R⁵ is C₃-C₇ cycloalkyl.

In some embodiments R⁵ is C₂-C₆ alkenyl.

In some embodiments R⁵ is C₂-C₆ alkynyl.

In some embodiments R^(6a) is hydrogen.

In some embodiments R^(6a) is optionally substituted C₁-C₆ alkyl.

In some embodiments R^(6a) is optionally substituted C₃-C₇ branchedalkyl.

In some embodiments R^(6a) is optionally substituted C₃-C₇ cycloalkyl.

In some embodiments R^(6a) is optionally substituted C₂-C₆ alkenyl.

In some embodiments R^(6a) is optionally substituted C₂-C₆ alkynyl.

In some embodiments R^(6b) is hydrogen.

In some embodiments R^(6b) is optionally substituted C₁-C₆ alkyl.

In some embodiments R^(6b) is optionally substituted C₃-C₇ branchedalkyl.

In some embodiments R^(6b) is optionally substituted C₃-C₇ cycloalkyl.

In some embodiments R^(6b) is optionally substituted C₂-C₆ alkenyl.

In some embodiments R^(6b) is optionally substituted C₂-C₆ alkynyl.

In some embodiments R^(6a) and R^(6b) are taken together with the atomto which they are bound to form an optionally substituted 6 memberedring.

In some embodiments m is 1.

In some embodiments m is 2.

In some embodiments m is 3.

In some embodiments R⁷ is COC R^(8a)R^(8b)(NHR⁹).

In some embodiments R⁷ is

In some embodiments R⁷ is

In some embodiments R^(8a) is hydrogen.

In some embodiments R^(8a) is CH₃.

In some embodiments R^(8a) is CH(CH₃)₂.

In some embodiments R^(8a) is CH₂CH(CH₃)₂.

In some embodiments R^(8a) is CH(CH₃)CH₂CH₃.

In some embodiments R^(8a) is CH₂OH.

In some embodiments R^(8a) is CH(OH)CH₃.

In some embodiments R^(8a) is CH₂Ph.

In some embodiments R^(8a) is CH₂(4-OH-Ph).

In some embodiments R^(8a) is (CH₂)₄NH₂.

In some embodiments R^(8a) is (CH₂)₃NHC(NH₂)NH.

In some embodiments R^(8a) is CH₂(3-indole).

In some embodiments R^(8a) is CH₂(5-imidazole).

In some embodiments R^(8a) is CH₂CO₂H.

In some embodiments R^(8a) is CH₂CH₂CO₂H.

In some embodiments R^(8a) is CH₂CONH₂.

In some embodiments R^(8a) is CH₂CH₂CONH₂.

In some embodiments R^(8b) is hydrogen.

In some embodiments R^(8b) is CH₃.

In some embodiments R^(8b) is CH(CH₃)₂.

In some embodiments R^(8b) is CH₂CH(CH₃)₂.

In some embodiments R^(8b) is CH(CH₃)CH₂CH₃.

In some embodiments R^(8b) is CH₂OH.

In some embodiments R^(8b) is CH(OH)CH₃.

In some embodiments R^(8b) is CH₂Ph.

In some embodiments R^(8b) is CH₂(4-OH-Ph).

In some embodiments R^(8b) is (CH₂)₄NH₂.

In some embodiments R^(8b) is (CH₂)₃NHC(NH₂)NH.

In some embodiments R^(8b) is CH₂(3-indole).

In some embodiments R^(8b) is CH₂(5-imidazole).

In some embodiments R^(8b) is CH₂CO₂H.

In some embodiments R^(8b) is CH₂CH₂CO₂H.

In some embodiments R^(8b) is CH₂CONH₂.

In some embodiments R^(8b) is CH₂CH₂CONH₂.

In some embodiments R⁹ is hydrogen.

In some embodiments R⁹ is C₁-C₆ alkyl.

In some embodiments R⁹ is C₃-C₇ branched alkyl.

In some embodiments R⁹ is C₃-C₇ cycloalkyl.

In some embodiments R⁹ is C₂-C₆ alkenyl.

In some embodiments R⁹ is C₂-C₆ alkynyl.

In some embodiments Y is H₂.

In some embodiments Y is O.

In some embodiments R^(10a) is hydrogen.

In some embodiments R^(10a) is CH₃.

In some embodiments R^(10a) is CH₂CH₃.

In some embodiments R^(10a) is CH(CH₃)₂.

In some embodiments R^(10a) is CH₂CH(CH₃)₂.

In some embodiments R^(10a) is CH(CH₃)CH₂CH₃.

In some embodiments R^(10a) is CH₂OH.

In some embodiments R^(10a) is CH₂OCH₂Ph.

In some embodiments R^(10a) is CH(OH)CH₃.

In some embodiments R^(10a) is CH₂Ph.

In some embodiments R^(10a) is CH₂(4-OH-Ph).

In some embodiments R^(10a) is (CH₂)₄NH₂.

In some embodiments R^(10a) is (CH₂)₃NHC(NH₂)NH.

In some embodiments R^(10a) is CH₂(3-indole).

In some embodiments R^(10a) is CH₂(5-imidazole).

In some embodiments R^(10a) is CH₂(CCH).

In some embodiments R^(10a) is CH₂(cyclohexyl),

In some embodiments R^(10a) is CH₂CO₂H.

In some embodiments R^(10a) is CH₂CH₂CO₂H.

In some embodiments R^(10a) is CH₂CONH₂.

In some embodiments R^(10a) is CH₂CH₂CONH₂.

In some embodiments R^(10b) is hydrogen.

In some embodiments R^(10b) is CH₃.

In some embodiments R^(10b) is CH₂CH₃.

In some embodiments R^(10b) is CH(CH₃)₂.

In some embodiments R^(10b) is CH₂CH(CH₃)₂.

In some embodiments R^(10b) is CH(CH₃)CH₂CH₃.

In some embodiments R^(10b) is CH₂OH.

In some embodiments R^(10b) is CH₂OCH₂Ph.

In some embodiments R^(10b) is CH(OH)CH₃.

In some embodiments R^(10b) is CH₂Ph.

In some embodiments R^(10b) is CH₂(4-OH-Ph).

In some embodiments R^(10b) is (CH₂)₄NH₂.

In some embodiments R^(10b) is (CH₂)₃NHC(NH₂)NH.

In some embodiments R^(10b) is CH₂(3-indole).

In some embodiments R^(10b) is CH₂(5-imidazole).

In some embodiments R^(10b) is CH₂(CCH).

In some embodiments R^(10b) is CH₂(cyclohexyl),

In some embodiments R^(10b) is CH₂CO₂H.

In some embodiments R^(10b) is CH₂CH₂CO₂H.

In some embodiments R^(10b) is CH₂CONH₂.

In some embodiments R^(10b) is CH₂CH₂CONH₂.

In some embodiments R^(10a) and R^(10b) are taken together with the atomto which they are bound to form an optionally substituted three to sixmembered saturated carbocyclic ring.

In some embodiments R¹¹ is hydrogen.

In some embodiments R¹¹ is of C₁-C₆ alkyl.

In some embodiments R¹¹ is C₃-C₇ branched alkyl.

In some embodiments R¹¹ is C₃-C₇ cycloalkyl.

In some embodiments R¹¹ is C₂-C₆ alkenyl.

In some embodiments R¹¹ is C₁-C₆ haloalkyl.

In some embodiments R¹¹ is C₂-C₆ alkynyl.

In some embodiments R^(10a) and R¹¹ are taken together with the atoms towhich they are bound to form an optionally substituted four to sixmembered ring containing one nitrogen atom, and R¹² is not hydrogen.

In some embodiments R^(10b) and R¹¹ are taken together with the atoms towhich they are bound to form an optionally substituted four to sixmembered ring containing one nitrogen atom, and R¹² is not hydrogen.

In some embodiments R¹² is hydrogen.

In some embodiments R¹² is C₁-C₆ alkyl.

In some embodiments R¹² is COCR^(13a)R^(13b)NR^(15a)R^(15b).

In some embodiments R¹² is COCR^(13a)R^(13b)OR¹⁴.

In some embodiments R¹² is SO₂CR^(13a)R^(13b)NR^(15a)R^(15b).

In some embodiments R¹² is COCR^(13a)R^(13b)NHSO₂R^(15a).

In some embodiments R¹² is

In some embodiments R¹² is

In some embodiments R¹² is

In some embodiments R¹² is

In some embodiments R¹² is

In some embodiments R¹² is

In some embodiments R¹² is

In some embodiments R¹² is (CR^(19a)R^(19b))_(q)NHR²⁰.

In some embodiments R¹¹ and R¹² are taken together with the atom towhich they are bound to form an optionally substituted four to sixmembered saturated heterocyclic ring containing a nitrogen atom andoptionally containing an additional heteroatom from the group consistingof N and O.

In some embodiments R^(13a) is hydrogen.

In some embodiments R^(13a) is CH₃.

In some embodiments R^(13a) is CH₂CH₃.

In some embodiments R^(13a) is CH₂CH₂CH₃.

In some embodiments R^(13a) is CH₂CCH.

In some embodiments R^(13a) is CH(CH₃)₂.

In some embodiments R^(13a) is CH₂CH(CH₃)₂.

In some embodiments R^(13a) is CH(CH₃)CH₂CH₃.

In some embodiments R^(13a) is CH₂OH.

In some embodiments R^(13a) is CH₂OCH₂Ph.

In some embodiments R^(13a) is CH₂CH₂OCH₂Ph.

In some embodiments R^(13a) is CH(OH)CH₃.

In some embodiments R^(13a) is CH₂Ph.

In some embodiments R^(13a) is CH₂(cyclohexyl).

In some embodiments R^(13a) is CH₂(4-OH-Ph).

In some embodiments R^(13a) is (CH₂)₄NH₂.

In some embodiments R^(13a) is (CH₂)₃NHC(NH₂)NH.

In some embodiments R^(13a) is CH₂(3-indole).

In some embodiments R^(13a) is CH₂(5-imidazole).

In some embodiments R^(13a) is CH₂CO₂H.

In some embodiments R^(13a) is CH₂CH₂CO₂H.

In some embodiments R^(13a) is CH₂CONH₂.

In some embodiments R^(13a) is CH₂CH₂CONH₂.

In some embodiments R^(13b) is hydrogen.

In some embodiments R^(13b) is CH₃.

In some embodiments R^(13b) is CH₂CH₃.

In some embodiments R^(13b) is CH₂CH₂CH₃.

In some embodiments R^(13b) is CH₂CCH.

In some embodiments R^(13b) is CH(CH₃)₂.

In some embodiments R^(13b) is CH₂CH(CH₃)₂.

In some embodiments R^(13b) is CH(CH₃)CH₂CH₃.

In some embodiments R^(13b) is CH₂OH.

In some embodiments R^(13b) is CH₂OCH₂Ph.

In some embodiments R^(13b) is CH₂CH₂OCH₂Ph.

In some embodiments R^(13b) is CH(OH)CH₃.

In some embodiments R^(13b) is CH₂Ph.

In some embodiments R^(13b) is CH₂(cyclohexyl).

In some embodiments R^(13b) is CH₂(4-OH-Ph).

In some embodiments R^(13b) is (CH₂)₄NH₂.

In some embodiments R^(13b) is (CH₂)₃NHC(NH₂)NH.

In some embodiments R^(13b) is CH₂(3-indole).

In some embodiments R^(13b) is CH₂(5-imidazole).

In some embodiments R^(13b) is CH₂CO₂H.

In some embodiments R^(13b) is CH₂CH₂CO₂H.

In some embodiments R^(13b) is CH₂CONH₂.

In some embodiments R^(13b) is CH₂CH₂CONH₂.

In some embodiments R^(13a) and R^(13b) are taken together with the atomto which they are bound to form an optionally substituted three to sixmembered saturated carbocyclic ring.

In some embodiments R^(13a) and R^(13b) are taken together with the atomto which they are bound to form an optionally substituted six memberedsaturated heterocyclic ring with one O atom within the ring.

In some embodiments R^(13a) and R¹⁴ are taken together with the atoms towhich they are bound to form an optionally substituted four to sixmembered ring containing one nitrogen atom.

In some embodiments R^(13a) and R^(15a) are taken together with theatoms to which they are bound to form an optionally substituted four tosix membered ring containing one nitrogen atom. In some embodiments Y¹is

In some embodiments Y¹ is H₂.

In some embodiments Y¹ is O.

In some embodiments Y¹ is —H/—OCH₂Ph.

In some embodiments R¹⁴ is hydrogen.

In some embodiments R¹⁴ is C₁-C₆ alkyl.

In some embodiments R¹⁴ is C₃-C₇ branched alkyl.

In some embodiments R¹⁴ is C₃-C₇ cycloalkyl.

In some embodiments R¹⁴ is C₂-C₆ alkenyl.

In some embodiments R¹⁴ is C₂-C₆ alkynyl.

In some embodiments R^(15a) is hydrogen.

In some embodiments R^(15a) is C₁-C₆ alkyl.

In some embodiments R^(15a) is C₃-C₇ branched alkyl.

In some embodiments R^(15a) is C₃-C₇ cycloalkyl.

In some embodiments R^(15a) is C₂-C₆ alkenyl.

In some embodiments R^(15a) is C₂-C₆ alkynyl.

In some embodiments R^(15a) is C₁-C₆ fluoroalkyl.

In some embodiments R^(15a) is COR²¹.

In some embodiments R^(15a) is CH₂R²¹.

In some embodiments R^(15a) is SO₂R²².

In some embodiments R^(15a) is an optionally substituted four to sixmembered saturated heterocyclic ring containing a heteroatom selectedfrom the group consisting of NR²⁴ and O,

In some embodiments R^(15a) is COCHR²³NH₂.

In some embodiments R^(15a) is

In some embodiments R^(15a) is

In some embodiments R^(15a) is

In some embodiments R^(15a) is

In some embodiments R^(15a) is

In some embodiments R^(15a) is

In some embodiments R^(15a) is

In some embodiments R^(15a) is

In some embodiments R^(15a) is

In some embodiments R^(15b) is hydrogen.

In some embodiments R^(15b) is C₁-C₆ alkyl.

In some embodiments R^(15b) is C₃-C₇ branched alkyl.

In some embodiments R^(15b) is C₃-C₇ cycloalkyl.

In some embodiments R^(15b) is C₂-C₆ alkenyl.

In some embodiments R^(15b) is C₂-C₆ alkynyl.

In some embodiments R^(15b) is C₁-C₆ fluoroalkyl.

In some embodiments R^(15b) is COR²¹.

In some embodiments R^(15b) is CH₂R²¹.

In some embodiments R^(15b) is SO₂R²².

In some embodiments R^(15b) is an optionally substituted four to sixmembered saturated heterocyclic ring containing a heteroatom selectedfrom the group consisting of NR²⁴ and O,

In some embodiments R^(15b) is COCHR²³NH₂.

In some embodiments R^(15b) is

In some embodiments R^(15b) is

In some embodiments R^(15b) is

In some embodiments R^(15b) is

In some embodiments R^(15b) is

In some embodiments R^(15b) is

In some embodiments R^(15b) is

In some embodiments R^(15b) is

In some embodiments R^(15b) is

In some embodiments R^(15a) and R^(15b) are taken together with the atomto which they are bound to form an optionally substituted four to sixmembered saturated heterocyclic ring optionally containing one O atomwithin the ring.

In some embodiments R¹⁶ is CH₂.

In some embodiments R¹⁶ is O.

In some embodiments R¹⁶ is C═O.

In some embodiments R¹⁶ is NH.

In some embodiments R¹⁷ is hydrogen.

In some embodiments R¹⁷ is C₁-C₆ alkyl.

In some embodiments R¹⁷ is C₃-C₇ branched alkyl.

In some embodiments R¹⁷ is C₃-C₇ cycloalkyl.

In some embodiments R¹⁷ is C₂-C₆ alkenyl.

In some embodiments R¹⁷ is C₂-C₆ alkynyl.

In some embodiments R¹⁸ is hydrogen.

In some embodiments R¹⁸ is C₁-C₆ alkyl.

In some embodiments R¹⁸ is C₃-C₇ branched alkyl.

In some embodiments R¹⁸ is C₃-C₇ cycloalkyl.

In some embodiments R¹⁸ is C₂-C₆ alkenyl.

In some embodiments R¹⁸ is C₂-C₆ alkynyl.

In some embodiments R¹⁷ and R¹⁸ are taken together with the atoms towhich they are bound to form an optionally substituted five or sixmembered ring containing two nitrogen atoms.

In some embodiments R^(19a) is hydrogen.

In some embodiments R^(19a) is optionally substituted C₁-C₆ alkyl.

In some embodiments R^(19a) is optionally substituted C₃-C₇ branchedalkyl.

In some embodiments R^(19a) is optionally substituted C₃-C₇ cycloalkyl.

In some embodiments R^(19a) is optionally substituted C₂-C₆ alkenyl.

In some embodiments R^(19a) is optionally substituted C₂-C₆ alkynyl.

In some embodiments R^(19b) is hydrogen.

In some embodiments R^(19b) is optionally substituted C₁-C₆ alkyl.

In some embodiments R^(19b) is optionally substituted C₃-C₇ branchedalkyl.

In some embodiments R^(19b) is optionally substituted C₃-C₇ cycloalkyl.

In some embodiments R^(19b) is optionally substituted C₂-C₆ alkenyl.

In some embodiments R^(19b) is optionally substituted C₂-C₆ alkynyl.

In some embodiments R^(19a) and R^(19b) are taken together with the atomto which they are bound to form an optionally substituted 3 memberedcarbocyclic ring.

In some embodiments R^(19a) and R^(19b) are taken together with the atomto which they are bound to form an optionally substituted 4 memberedcarbocyclic ring.

In some embodiments R^(19a) and R^(19b) are taken together with the atomto which they are bound to form an optionally substituted 5 memberedcarbocyclic ring.

In some embodiments R^(19a) and R^(19b) are taken together with the atomto which they are bound to form an optionally substituted 6 memberedcarbocyclic ring.

In some embodiments R²⁰ is hydrogen.

In some embodiments R²⁰ is C₁-C₆ alkyl.

In some embodiments R²⁰ is C₃-C₇ branched alkyl.

In some embodiments R²⁰ is C₃-C₇ cycloalkyl.

In some embodiments R²⁰ is C₂-C₆ alkenyl.

In some embodiments R²⁰ is C₂-C₆ alkynyl.

In some embodiments q is 1.

In some embodiments q is 2.

In some embodiments R²¹ is hydrogen.

In some embodiments R²¹ is C₁-C₆ alkyl.

In some embodiments R²¹ is C₃-C₇ branched alkyl.

In some embodiments R²¹ is C₃-C₇ cycloalkyl.

In some embodiments R²¹ is C₂-C₆ alkenyl.

In some embodiments R²¹ is C₂-C₆ alkynyl.

In some embodiments R²¹ is C₁-C₆ fluoroalkyl.

In some embodiments R²¹ is optionally substituted aryl.

In some embodiments R²¹ is optionally substituted heteroaryl.

In some embodiments R²² is C₁-C₆ alkyl.

In some embodiments R²² is C₃-C₇ branched alkyl.

In some embodiments R²² is C₃-C₇ cycloalkyl.

In some embodiments R²² is C₂-C₆ alkenyl.

In some embodiments R²² is C₂-C₆ alkynyl.

In some embodiments R²² is optionally substituted aryl.

In some embodiments R²² is optionally substituted heteroaryl

In some embodiments R²³ is hydrogen.

In some embodiments R²³ is CH₃.

In some embodiments R²³ is CH₂CH₃.

In some embodiments R²³ is CH₂CH₂CH₃.

In some embodiments R²³ is CH₂CCH.

In some embodiments R²³ is CH(CH₃)₂.

In some embodiments R²³ is CH₂CH(CH₃)₂.

In some embodiments R²³ is CH(CH₃)CH₂CH₃.

In some embodiments R²³ is CH₂OH.

In some embodiments R²³ is CH₂OCH₂Ph.

In some embodiments R²³ is CH₂CH₂OCH₂Ph.

In some embodiments R²³ is CH(OH)CH₃.

In some embodiments R²³ is CH₂Ph.

In some embodiments R²³ is CH₂(cyclohexyl).

In some embodiments R²³ is CH₂(4-OH-Ph).

In some embodiments R²³ is (CH₂)₄NH₂.

In some embodiments R²³ is (CH₂)₃NHC(NH₂)NH.

In some embodiments R²³ is CH₂(3-indole).

In some embodiments R²³ is CH₂(5-imidazole).

In some embodiments R²³ is CH₂CO₂H.

In some embodiments R²³ is CH₂CH₂CO₂H.

In some embodiments R²³ is CH₂CONH₂.

In some embodiments R²³ is CH₂CH₂CONH₂.

In some embodiments R²⁴ is hydrogen.

In some embodiments R²⁴ is C₁-C₆ alkyl.

In some embodiments R²⁴ is C₃-C₇ branched alkyl.

In some embodiments R²⁴ is C₃-C₇ cycloalkyl.

In some embodiments R²⁴ is C₂-C₆ alkenyl.

In some embodiments R²⁴ is C₂-C₆ alkynyl.

In some embodiments R²⁴ is optionally substituted aryl.

In some embodiments R²⁴ is optionally substituted heteroaryl.

In some embodiments R²⁴ is COR²⁵.

In some embodiments R²⁴ is SO₂—C₁₋₆ alkyl.

In some embodiments R²⁵ is hydrogen.

In some embodiments R²⁵ is C₁-C₆ alkyl.

In some embodiments R²⁵ is C₃-C₇ branched alkyl.

In some embodiments R²⁵ is C₃-C₇ cycloalkyl.

In some embodiments R²⁵ is C₂-C₆ alkenyl.

In some embodiments R²⁵ is C₂-C₆ alkynyl.

In some embodiments R²⁵ is optionally substituted aryl.

In some embodiments R²⁵ is optionally substituted heteroaryl.

In some embodiments R²⁵ is C₁-C₆ alkoxy.

In some embodiments R²⁵ is C₁-C₆ alkylamino.

Exemplary non-limiting embodiments of the invention include

-   2-(methylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl)acetamide;-   (S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pyrrolidine-2-carboxamide;-   (R)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide;-   3-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl) propanamide;-   1-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl) cyclopropane-1-carboxamide;-   (S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)azetidine-2-carboxamide;-   2-amino-2-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl)propanamide;-   (S)-2-(methylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl)propanamide;-   (R)-2-(methylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl)propanamide;-   (R)-2-amino-3-hydroxy-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl)propanamide;-   (R)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)pent-4-ynamide;-   (S)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl)pent-4-ynamide;-   (R)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)pyrrolidine-2-carboxamide;-   1-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclobutane-1-carboxamide;-   (S)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl)pentanamide;-   (R)-2-amino-3-methyl-N-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)butanamide;-   (S)-4-oxo-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pyrrolidine-2-carboxamide;-   (S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)piperidine-2-carboxamide;-   (S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)morpholine-3-carboxamide;-   (R)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)morpholine-3-carboxamide;-   (R)-2-amino-4-methyl-N-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)pentanamide;-   (R)-4-oxo-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)piperidine-2-carboxamide;-   4-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)tetrahydro-2H-pyran-4-carboxamide;-   (R)-2-amino-N1-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl)pentanediamide;-   (R)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl)-3-phenylpropanamide;-   (R)-2-amino-3-cyclohexyl-N-(2-oxo-2-((6-(trifluoro methoxy)benzo[d]    thiazol-2-yl)amino)ethyl)propanamide;-   (R)-2-amino-3-(benzyloxy)-N-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide;-   (S)-2-amino-3-(benzyloxy)-N-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide;-   (R)-2-amino-3-(1H-indol-3-yl)-N-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide;-   (2S,4R)-4-(benzyloxy)-N-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)pyrrolidine-2-carboxamide;-   (S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)piperazine-2-carboxamide;-   (R)-2-amino-4-(benzyloxy)-N-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)butanamide;-   (R)-1-(N,N-dimethyl-L-valyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(L-valyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-D-valyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)    pyrrolidine-2-carboxamide;-   (R)-1-glycinyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)    pyrrolidine-2-carboxamide;-   (R)-1-N-ethylglycinyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)    pyrrolidine-2-carboxamide;-   (R)-1-N-isopropylglycinyl-N-(6-(trifluoromethoxy)    benzo[d]thiazol-2-yl) pyrrolidine-2-carboxamide;-   (R)-1-N-t-butylglycinyl-N-(6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(3-amino-2,2-dimethylpropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(1-(aminomethyl)cyclopropane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(1-(aminomethyl)cyclopentane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(1-(aminomethyl)cyclohexane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(3-amino-2,2-dimethylpropanoyl)-N-(6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(1-(aminomethyl)cyclopropane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(1-(aminomethyl)cyclopentane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(D-valyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(L-valyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-glycyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(D-alanyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(methylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(ethylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(isopropylglycyl)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(tert-butylglycyl)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(D-leucyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-glycyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide;-   (S)-1-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)azetidine-2-carboxamide;-   (S)-1-(1-(aminomethyl)cyclopropane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide;-   (S)-1-(1-(aminomethyl)cyclopentane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide;-   (S)-1-glycyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamide;-   (S)-1-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)piperidine-2-carboxamide;-   (S)-1-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)piperidine-2-carboxamide;-   (R)-1-(methylglycyl)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)piperidine-2-carboxamide;-   1-(2-aminoacetamido)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)cyclopropane-1-carboxamide;-   1-(2-(methylamino)acetamido)-N-(6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide;-   1-(2-aminoacetamido)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)cyclobutane-1-carboxamide;-   1-(2-(methylamino)acetamido)-N-(6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide;-   1-(3-amino-2,2-dimethylpropanamido)-N-(6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide;-   1-(aminomethyl)-N-(1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)    cyclopentane-1-carboxamide;-   1-(2-(isopropylamino)acetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide;-   1-(2-(isopropylamino)acetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide;-   1-(aminomethyl)-N-(1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)    cyclohexane-1-carboxamide;-   (R)-1-(2-aminopropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide;-   (R)-1-(2-amino-3-methylbutanamido)-N-(6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide;-   (S)-2-(2-aminoacetamido)-3-phenyl-N-(6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)propanamide;-   (S)-2-(2-(methylamino)acetamido)-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide;-   (S)-2-((R)-2-aminopropanamido)-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide;-   (S)-2-((S)-2-aminopropanamido)-3-phenyl-N-(6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)propanamide;-   (R)-2-amino-3-methyl-N—((S)-1-oxo-3-phenyl-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)butanamide;-   (S)-2-amino-2-methyl-N-(1-oxo-3-phenyl-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamide;-   (S)-1-amino-N-(1-oxo-3-phenyl-1-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclopropane-1-carboxamide;-   (S)-1-amino-N-(1-oxo-3-phenyl-1-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclobutane-1-carboxamide;-   1-(3-amino-2,2-dimethylpropanamido)-N-(6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide;-   (R)-2-(2-aminopropanamido)-2-methyl-N-(6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)propanamide;-   (S)-2-(2-aminopropanamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide;-   2-(2-aminoacetamido)-2-methyl-N-(6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)propanamide;-   (R)-2-amino-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)propan-2-yl)-3-phenylpropanamide;-   (S)-2-amino-3-(benzyloxy)-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamide;-   1-amino-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclopropane-1-carboxamide;-   1-amino-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclobutane-1-carboxamide;-   2-amino-2-methyl-N-(2-methyl-1-oxo-1-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamide;-   3-amino-2,2-dimethyl-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamide;-   1-(aminomethyl)-N-(2-methyl-1-oxo-1-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclopropane-1-carboxamide;-   1-(aminomethyl)-N-(2-methyl-1-oxo-1-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclopentane-1-carboxamide;-   1-(aminomethyl)-N-(2-methyl-1-oxo-1-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclohexane-1-carboxamide;-   2-methyl-2-(2-(methylamino)acetamido)-N-(6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)propanamide;-   2-(2-(ethylamino)acetamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide;-   2-(2-(isopropylamino)acetamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide;-   2-(2-(tert-butylamino)acetamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide;-   (S)-2-(2-aminoacetamido)-N-(6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)propanamide;-   (S)-2-amino-N—((S)-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamide;-   (R)-2-amino-N—((S)-1-oxo-1-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)propan-2-yl)propanamide;-   3-Amino-N,2,2-trimethyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide;-   1-(aminomethyl)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclopropane-1-carboxamide;-   1-(aminomethyl)-N-methyl-N-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclopentane-1-carboxamide;-   1-(aminomethyl)-N-methyl-N-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexane-1-carboxamide;-   N-methyl-2-(methylamino)-N-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide;-   2-(ethylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide;-   2-(isopropylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide;-   2-(tert-butylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide;-   2-(dimethylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)    amino)ethyl)acetamide;-   2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino) ethyl)acetamide;-   (S)-2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino) ethyl)propanamide;-   (R)-2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)    ethyl)propanamide;-   3-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)    propanamide;-   2-amino-N-ethyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)    ethyl)acetamide;-   2-amino-N-isopropyl-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl)acetamide;-   2-(aminomethyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)benzamide;-   tert-butyl    (4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)carbamate;-   4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide;-   (S)—N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)    pyrrolidine-2-carboxamide;-   (S)-2-amino-4-methyl-N-(4-oxo-4-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino) butyl)pentanamide;-   4-(2-aminoacetamido)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)butanamide;-   (S)-4-(2-aminopropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide;-   (S)-2-amino-3-methyl-N-(4-oxo-4-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino) butyl)butanamide;-   (S)-5-oxo-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)    pyrrolidine-2-carboxamide;-   (2S,3S)-2-amino-3-methyl-N-(4-oxo-4-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl) amino)butyl)pentanamide;-   (S)-4-amino-5-oxo-5-((4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)    amino)pentanoic acid;-   (S)-2-amino-4-(methylthio)-N-(4-oxo-4-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)butyl)butanamide;-   (S)-4-(2-amino-3-phenylpropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide;-   (S)-3-amino-4-oxo-4-((4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)    butyl)amino)butanoic acid;-   (S)-4-amino-5-oxo-5-((4-oxo-4-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)butyl) amino)pentanoic acid;-   (S)-4-(2-amino-3-(1H-indol-3-yl)propanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide;-   (S)—N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)    methyl)pyrrolidine-2-carboxamide;-   (S)—N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)    ethyl)cyclohexyl) methyl)pyrrolidine-2-carboxamide;-   (S)-2-amino-4-methyl-N-((1-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino) ethyl)cyclohexyl)methyl)pentanamide;-   (S)-2-amino-3-methyl-N-((1-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)butanamide;-   2-amino-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)    ethyl) cyclohexyl)methyl)acetamide;-   (S)-2-amino-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl) cyclohexyl)methyl)propanamide;-   2-(methylamino)-N-((1-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl) cyclohexyl)methyl)acetamide;-   (R)-2-amino-3-methyl-N-((1-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)    ethyl)cyclohexyl)methyl)butanamide;-   (S)-5-oxo-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)    cyclohexyl)methyl)pyrrolidine-2-carboxamide;-   (S)-2-amino-N1-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)    cyclohexyl)methyl)pentanediamide;-   (S)-2-amino-4-(methylthio)-N-((1-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)butanamide;-   (S)-2-amino-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl) cyclohexyl)methyl)-3-phenylpropanamide;-   (S)-3-amino-4-oxo-4-(((1-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino) ethyl)cyclohexyl)methyl)amino)butanoic    acid;-   (S)-4-amino-5-oxo-5-(((1-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino) ethyl)cyclohexyl)methyl)amino)pentanoic    acid;-   (S)-2-amino-3-(1H-indol-3-yl)-N-((1-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)propanamide;-   (R)-2-amino-3-methyl-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)    butyl)butanamide;-   (R)—N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)pyrrolidine-2-carboxamide;-   (R)-5-oxo-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)    pyrrolidine-2-carboxamide;-   (R)-2-amino-3-methyl-N-((1-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)    cyclohexyl)methyl)butanamide;-   (S)—N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)    methyl)pyrrolidine-2-carboxamide;-   (R)-5-oxo-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)cyclohexyl)    methyl)pyrrolidine-2-carboxamide;-   4-amino-3,3-dimethyl-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)butanamide;-   (S)-3-(benzyloxy)-2-morpholino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide;-   (S)-3-(benzyloxy)-2-(dimethylamino)-N-(6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)propanamide;-   (S)-1-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide;-   2-(ethylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl)acetamide;-   2-(isopropylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide;-   (R)-1-(1-(aminomethyl)cyclohexane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)pyrrolidine-2-carboxamide;-   N-methyl-2-(methylsulfonamido)-N-(2-oxo-2-((6-(trifluoro    methoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide;-   2-(tert-butoxy)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl)acetamide;-   N,4,4-trimethyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl) pentanamide;-   tert-Butyl    (2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)(1-(trifluoromethyl)cyclopropyl)carbamate;-   N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)-2-((1-(trifluoromethyl)cyclopropyl)amino)acetamide;-   N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)-2-((2,2,2-trifluoroethyl)amino)acetamide    hydrochloride;-   2-acetamido-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl) acetamide;-   N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)propionamide;-   N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)butyramide;-   N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)isobutyramide;-   N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)benzamide;-   2,2,2-trifluoro-N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)    benzo[d]thiazol-2-yl)amino)ethyl) amino)-2-oxoethyl)acetamide;-   N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetamide;-   2-(2-oxopiperazin-1-yl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide;-   (S)—N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl) piperazine-2-carboxamide;-   (R)—N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)amino)ethyl) piperazine-2-carboxamide;-   Benzyl    (2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate;-   2-aminoethyl (6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamate;-   Benzyl    ethyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)    ethyl)carbamate;-   2-(Ethylamino)ethyl    (6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamate;-   Benzyl    methyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)    ethyl)carbamate;-   2-(Methylamino)ethyl    (6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamate;-   Benzyl    isopropyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate;-   2-(Isopropylamino)ethyl (6-(trifluoromethoxy)benzo[d]    thiazol-2-yl)carbamate;-   (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (5-(trifluoro    methoxy)benzo[d]thiazol-2-yl)carbamate;-   4-amino-2,2-dimethyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide;-   (S)-2-amino-N1,N5-bis(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pentanediamide;-   2-(dimethylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide;-   and 1,3-bis(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)urea.

Exemplary embodiments include compounds having the formula (I) through(XVI) or a pharmaceutically acceptable salt form thereof, in combinationwith an anticancer agent. Exemplary embodiments of anticancer agentsinclude but are not limited to Vemurafenib, Ipilimumab, Masitinib,Sorafenib, Lenalidomide, Oblimersen, Trametinib, Dabrafenib, RO5185426,Veliparib, Bosentan, YM155, CNTO 95, CR011-vcMMAE, CY503, Lenvatinib,Avastin, Tasidotin, Ramucirumab, IPI-504, Tasisulam, KW2871, MPC-6827,RAF265, Dovitinib, Everolimus, MEK162, BKM120, Nilotinib, Reolysin,825A, Tremelimumab, PI-88, Elesclomol, STA9090, and Allovectin-7.

For the purposes of the present invention, a compound depicted by theracemic formula will stand equally well for either of the twoenantiomers or mixtures thereof, or in the case where a second chiralcenter is present, all diastereomers.

For the purposes of the present invention, a compound depicted by theracemic formula will stand equally well for either of the twoenantiomers or mixtures thereof, or in the case where a second chiralcenter is present, all diastereomers.

In all of the embodiments provided herein, examples of suitable optionalsubstituents are not intended to limit the scope of the claimedinvention. The compounds of the invention may contain any of thesubstituents, or combinations of substituents, provided herein.

Process

Compounds of the present teachings can be prepared in accordance withthe procedures outlined herein, from commercially available startingmaterials, compounds known in the literature, or readily preparedintermediates, by employing standard synthetic methods and proceduresknown to those skilled in the art. Standard synthetic methods andprocedures for the preparation of organic molecules and functional grouptransformations and manipulations can be readily obtained from therelevant scientific literature or from standard textbooks in the field.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions can vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures. Those skilled in the art of organic synthesiswill recognize that the nature and order of the synthetic stepspresented can be varied for the purpose of optimizing the formation ofthe compounds described herein.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C), infrared spectroscopy, spectrophotometry(e.g., UV-visible), mass spectrometry, or by chromatography such as highpressure liquid chromatography (HPLC), gas chromatography (GC),gel-permeation chromatography (GPC), or thin layer chromatography (TLC).

Preparation of the compounds can involve protection and deprotection ofvarious chemical groups. The need for protection and deprotection andthe selection of appropriate protecting groups can be readily determinedby one skilled in the art. The chemistry of protecting groups can befound, for example, in Greene et al., Protective Groups in OrganicSynthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of whichis incorporated by reference herein for all purposes.

The reactions or the processes described herein can be carried out insuitable solvents which can be readily selected by one skilled in theart of organic synthesis. Suitable solvents typically are substantiallynonreactive with the reactants, intermediates, and/or products at thetemperatures at which the reactions are carried out, i.e., temperaturesthat can range from the solvent's freezing temperature to the solvent'sboiling temperature. A given reaction can be carried out in one solventor a mixture of more than one solvent. Depending on the particularreaction step, suitable solvents for a particular reaction step can beselected.

The compounds of these teachings can be prepared by methods known in theart of organic chemistry. The reagents used in the preparation of thecompounds of these teachings can be either commercially obtained or canbe prepared by standard procedures described in the literature. Forexample, compounds of the present invention can be prepared according tothe method illustrated in the General Synthetic Schemes:

General Synthetic Schemes for Preparation of Compounds

The reagents used in the preparation of the compounds of this inventioncan be either commercially obtained or can be prepared by standardprocedures described in the literature. In accordance with thisinvention, compounds in the genus may be produced by one of thefollowing reaction schemes. Compounds of formula (I) may be preparedaccording to the process outlined in schemes 1-21.

Riluzole (1), a known compound, is reacted with a compound of theformula (2), a known compound or a compound made by known methods, inthe presence of a coupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (3). Acompound of the formula (3) is reacted with an acid such astrifluoroacetic acid, hydrochloric acid, and the like in a solvent suchas methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,and the like to provide a compound of the formula (4).

A compound of the formula (4) is reacted with a compound of the formula(5), a known compound or a compound made by known methods, in thepresence of a coupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (6). Acompound of the formula (6) is reacted with an acid such astrifluoroacetic acid, hydrochloric acid, and the like in a solvent suchas methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,and the like to provide a compound of the formula (7).

A compound of the formula (4) is reacted with a compound of (8), a knowncompound or a compound made by known methods, in the presence of acoupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (9).

A compound of the formula (4) is reacted with a compound of (10), aknown compound or a compound made by known methods, in the presence of acoupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (11). Acompound of the formula (11) is reacted with an acid such astrifluoroacetic acid, hydrochloric acid, and the like in a solvent suchas methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,and the like to provide a compound of the formula (12).

A compound of the formula (4) is reacted with a compound of (13), aknown compound or a compound made by known methods, in the presence of acoupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (14).

A compound of the formula (4) is reacted with a compound of (15), aknown compound or a compound made by known methods, in the presence of acoupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (16). Acompound of the formula (16) is reacted with an acid such astrifluoroacetic acid, hydrochloric acid, and the like in a solvent suchas methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,and the like to provide a compound of the formula (17).

Riluzole (1), a known compound, is reacted with a compound of theformula (18), a known compound or a compound made by known methods, inthe presence of a coupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (19). Acompound of the formula (19) is reacted with an acid such astrifluoroacetic acid, hydrochloric acid, and the like in a solvent suchas methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,and the like to provide a compound of the formula (20).

A compound of the formula (20) is reacted with a compound of (21), aknown compound or a compound made by known methods, in the presence of acoupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (22).

A compound of the formula (20) is reacted with a compound of (23), aknown compound or a compound made by known methods, in the presence of acoupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (24). Acompound of the formula (24) is reacted with an acid such astrifluoroacetic acid, hydrochloric acid, and the like in a solvent suchas methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,and the like to provide a compound of the formula (25).

A compound of the formula (20) is reacted with a compound of (26), aknown compound or a compound made by known methods, in the presence of acoupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (27).

A compound of the formula (20) is reacted with a compound of (28), aknown compound or a compound made by known methods, in the presence of acoupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (29). Acompound of the formula (29) is reacted with an acid such astrifluoroacetic acid, hydrochloric acid, and the like in a solvent suchas methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,and the like to provide a compound of the formula (30).

A compound of the formula (20) is reacted with a compound of (31), aknown compound or a compound made by known methods, in the presence of acoupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (32). Acompound of the formula (32) is reacted with an acid such astrifluoroacetic acid, hydrochloric acid, and the like in a solvent suchas methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,and the like to provide a compound of the formula (33).

A compound of the formula (20) is reacted with a compound of (34), aknown compound or a compound made by known methods, in the presence of acoupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (35). Acompound of the formula (35) is reacted with an acid such astrifluoroacetic acid, hydrochloric acid, and the like in a solvent suchas methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,and the like to provide a compound of the formula (36).

A compound of the formula (20) is reacted with a compound of (37), aknown compound or a compound made by known methods, in the presence of acoupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, N-methylmorpholine and the like, in a solventsuch as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylenechloride and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (38). Acompound of the formula (38) is reacted with an acid such astrifluoroacetic acid, hydrochloric acid, and the like in a solvent suchas methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,and the like to provide a compound of the formula (39).

A compound of the formula (25) is reacted with a compound of (40), aknown compound or a compound made by known methods, in the presence of abase such as triethylamine, diisopropylethylamine, N-methylmorpholineand the like, in a solvent such as N, N-dimethylformamide, 1,4-dioxane,tetrahydrofuran, methylene chloride and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (41).

A compound of the formula (42), a known compound or a compounds preparedby known methods, is reacted with triphosgene in the presence of asolvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran,methylene chloride, chloroform, and the like. The resulting product isthen reacted with a compound of the formula (1) in the presence of abase such as triethylamine, diisopropylethylamine, N-methylmorpholineand the like, in the presence of a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chlorideand the like, optionally with heating, optionally with microwaveirradiation to provide a compound of the formula (43). A compound of theformula (44) is reacted with hydrogen bromide in the presence of aceticacid, optionally in the presence of a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chlorideand the like, optionally with heating, optionally with microwaveirradiation to provide a compound of the formula (44).

A compound of the formula (45), a known compound or a compound preparedby known methods, is reacted with triphosgene in the presence of asolvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran,methylene chloride, chloroform, and the like to provide a compound ofthe formula (46). A compound of the formula (46) is reacted with acompound of the formula (1) in the presence of a base such astriethylamine, diisopropylethylamine, N-methylmorpholine, and the like,in the presence of a solvent such as N, N-dimethylformamide,1,4-dioxane, tetrahydrofuran, methylene chloride and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (43).

A compound of the formula (48), a known compound or a compound preparedby known methods, is reacted with a compound of the formula (49), aknown compound or a compounds prepared using known methods, in thepresence of a solvent such as N, N-dimethylformamide, 1,4-dioxane,tetrahydrofuran, methylene chloride and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (50).

A compound of the formula (51), a known compound or a compound preparedby known methods, is reacted with a compound of the formula (52), aknown compound or a compounds prepared using known methods, in thepresence of a solvent such as N, N-dimethylformamide, 1,4-dioxane,tetrahydrofuran, methylene chloride and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (53).

A compound of the formula (54), a known compound or a compound preparedby known methods, is reacted with a compound of the formula (55), aknown compound or a compounds prepared using known methods, in thepresence of a base such as triethylamine, diisopropylethylamine,N-methylmorpholine and the like, in the presence of a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chlorideand the like, optionally with heating, optionally with microwaveirradiation to provide a compound of the formula (56). A compound of theformula (56) is reacted with a compound of the formula (57), a knowncompound or a compound prepared by known methods, in the presence of asolvent such as N, N-dimethylformamide, dimethylsulfoxide, 1,4-dioxane,tetrahydrofuran, methylene chloride and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (58).

A compound of the formula (56) is reacted with a compound of the formula(59), a known compound or a compound prepared by known methods wherein Mis a counter ion such as sodium, potassium, tetrabutyl ammonium, and thelike, in the presence of a solvent such as N, N-dimethylformamide,dimethylsulfoxide, 1,4-dioxane, tetrahydrofuran, methylene chloride andthe like, optionally with heating, optionally with microwave irradiationto provide a compound of the formula (60). A compound of the formula(60) is reacted with hydrogen in the presence of a catalyst such aspalladium on carbon, palladium on barium sulfate, palladium (II)acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran,1,4-dioxane, dichloromethane, chloroform, 1,2-dichloroethane,N,N-dimethylformamide, and the like, to provide a compound of theformula (61). A compound of the formula (61) is reacted with a compoundof the formula (62), a known compound or a compound prepared by knownmethods, in the presence of a hydride source such as sodium borohydride,sodium cyanoborohydride, sodium triacetoxy borohydride, and the like,optionally in the presence of an acid such as acetic acid,trifluoroacetic acid, formic acid, and the like, in an organic solventsuch as methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane,dichloromethane, chloroform, 1,2-dichloroethane, N,N-dimethylformamide,and the like, optionally with heating, optionally with microwaveirradiation to provide a compound of the formula (63). A compound of theformula (63) is reacted with a compound of the formula (62), a knowncompound or a compound prepared by known methods, in the presence of ahydride source such as sodium borohydride, sodium cyanoborohydride,

sodium triacetoxy borohydride, and the like, optionally in the presenceof an acid such as acetic acid, trifluoroacetic acid, formic acid, andthe like, in an organic solvent such as methanol, ethanol, ethylacetate, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform,1,2-dichloroethane, N,N-dimethylformamide, and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (64).

Schemes 1-21 describe the preparation of compounds containing chiralcenters. Those skilled in the art of organic synthesis will recognizethat the chemistry described in schemes 1-21 can be applied to preparethe enantiomer of the compounds described employing starting materialcontaining the opposite stereochemistry. In the case of compounds withmultiple chiral centers those skilled in the art of organic synthesiswill recognize that the chemistry described in schemes 1-21 can beemployed to prepare compounds of the disclosure from starting materialscontaining the desired chirality and each chiral center.

EXAMPLES

Example 1-267 provides methods for preparing representative compounds offormula (I). The skilled practitioner will know how to substitute theappropriate reagents, starting materials and purification methods knownto those skilled in the art, in order to prepare additional compounds ofthe present invention.

The following procedures were employed to purify and analyze compoundsof the disclosure. Those skilled in the art would understand thatalternate methods could be employed to analyze and purify the compoundsof the disclosure.

Method A: LC/MS data were determined with a Waters Alliance 2695 HPLC/MS(Waters Symmetry C18, 4.6×75 mm, 3.5 μm) with a 2996 diode arraydetector from 210-400 nm; the solvent system is 5-95% acetonitrile inwater (with 0.1% TFA) over nine minutes using a linear gradient, andretention times are in minutes. Mass spectrometry was performed on aWaters ZQ using electrospray in positive mode.

Method B: Preparative reversed phase HPLC was performed on a WatersSunfire column (19×50 mm, C18, 5 μm) with a 10 min mobile phase gradientof 10% acetonitrile/water to 90% acetonitrile/water with 0.1% TFA asbuffer using 214 and 254 nm as detection wavelengths. Injection andfraction collection were performed with a Gilson 215 liquid handlingapparatus using Trilution LC software.

Method C: LC/MS data were determined on a Shimadzu LC 20AD instrumentwith a Phenomenex Luna C18 (3 μm) 50×3.0 mm column. Mobile phaseconsisted of water and acetonitrile with 0.1% formic acid buffer.Gradient was 10-90% acetonitrile over three minutes and held at 90%acetonitrile for two minutes. Detection was performed on diode arraydetector from 210-400 nm and retention times are in minutes. Massspectra were determined on an Applied Biosystems MDS Sciex API 2000instrument using electrospray ionization.

Example 1: Synthesis of2-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide

To a solution of 2-amino-6-(trifluoromethoxy)benzimidazole (0.50 g, 2.1mmol), N-(t-butyloxycarbonyl) glycine (0.56 g, 3.2 mmol) andN,N-diisopropylethylamine (0.41 g, 3.2 mmol, 0.57 ml) indimethylformamide (7 ml) was added1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 1.2 g, 3.2 mmol) and the mixturestirred at 20° C. for 18 hours. Ethyl acetate (100 ml) was added and themixture was washed with water (2×75 ml), 1N HCl (75 ml), water (75 ml),1M sodium carbonate solution (75 ml) and brine. The organic layer wasdried over sodium sulfate and evaporated. The residue waschromatographed on silica gel eluted with a gradient of ethyl acetate inhexanes (50% to 75%) to leave the product as a white foamy solid (0.78g, 95%). LC/MS method A: R_(t)=5.92 min., (M+H)⁺=392. The product wasdissolved in 4N HCl/1,4-dioxane and stirred for 2 h. The solvents wereevaporated in an HCl compatible Genevac evaporator to leave a whitesolid mono HCl product (0.69 g, 100%, 95% overall yield). LC/MS methodA: R_(t)=3.53 min., (M+H)⁺=292.

Example 2: Synthesis of2-(Methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl) acetamidehydrochloride

2-(Methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl) acetamidehydrochloride was prepared according to the procedure of example 1 from2-amino-6-(trifluoromethoxy) benzimidazole (0.50 g, 2.1 mmol) andN-(t-butyloxycarbonyl)sarcosine (0.60 g, 3.2 mmol). Yield forintermediate=0.96 g (100%). LC/MS method A: R_(t)=5.92 min., (M+H)⁺=406.Yield for final product (0.82 g, 100%, 100% overall). LC/MS method A:R_(t)=3.60 min., (M+H)⁺=306.

Example 3: Synthesis of2-(Ethylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidehydrochloride

2-(Ethylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidehydrochloride was prepared according to the procedure of example 1 from2-amino-6-(trifluoromethoxy)benzimidazole (117 mg, 0.5 mmol) andN-t-butyloxycarbonyl-2-(ethylamino)acetic acid (122 mg, 0.6 mmol). Yieldfor Boc protected intermediate 182 mg (87%). LC/MS method A: R_(t)=6.20min., (M+H)⁺=420. Yield for final product (142 mg, 87% overall). LC/MSmethod A: R_(t)=3.67 min., (M+H)⁺=320.

Example 4: Synthesis of2-(Isopropylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidehydrochloride

2-(Isopropylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidehydrochloride was prepared according to the procedure of example 1 from2-amino-6-(trifluoromethoxy) benzimidazole (117 mg, 0.5 mmol) andN-t-butyloxycarbonyl-2-(isopropylamino)acetic acid (131 mg, 0.6 mmol).Yield for Boc protected intermediate 146 mg (67%). LC/MS method A:R_(t)=6.39 min., (M+H)⁺=434. Yield for final product (110 mg, 67%overall). LC/MS method A: R_(t)=3.76 min., (M+H)⁺=334.

Example 5: Synthesis of(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

To a solution of 2-amino-6-(trifluoromethoxy)benzimidazole (50 mg, 0.21mmol), N-t-butyloxycarbonyl-L-proline (69 mg, 0.32 mmol),1-Hydroxy-7-azabenzotriazole (42 mg, 0.32 mmol) andN,N-diisopropylethylamine (41 mg, 0.32 mmol, 57 μl) in N,N-dimethylformamide (0.35 ml) was added 2-chloro-1-methylpyridinium iodide (82 mg,0.32 mmol) and the yellow solution stirred for 72 hours. Water (0.25 ml)and methanol (1 ml) were added and the mixture was purified by reversephase HPLC (method B). The product fractions were combined and thesolvents were removed on a Genevac evaporator. This left 59 mg (59%) offoamy solid. LC/MS method A: R_(t)=6.21 min., (M+H)⁺=432. The productwas dissolved in 4N HCl/1,4-dioxane and stirred for 2 h. The solventswere evaporated in an HCl compatible Genevac evaporator to leave a whitesolid mono HCl product (45 mg, 100%, 59% overall yield). LC/MS method A:R_(t)=3.72 min., (M+H)⁺=332.

Example 6: Synthesis of(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 5 from2-amino-6-(trifluoromethoxy) benzimidazole (50 mg, 0.21 mmol) andN-t-butyloxycarbonyl-D-proline (69 mg, 0.32 mmol). Yield for Bocprotected intermediate 64 mg (71%). LC/MS method A: R_(t)=6.21 min.,(M+H)⁺=432. Yield for final product (46 mg, 60% overall). LC/MS methodA: R_(t)=3.72 min., (M+H)⁺=332.

Example 7: Synthesis of(R)-2-amino-3-phenyl-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)propanamide

(R)-2-amino-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide was prepared according to the procedure of example 5 from2-amino-6-(trifluoro methoxy) benzimidazole (100 mg, 0.42 mmol) andN-t-butyloxycarbonyl-D-phenylalanine (170 mg, 0.64 mmol). Yield for Bocprotected intermediate 91 mg (44%). LC/MS method A: R_(t)=6.67 min.,(M+H)⁺=482. Yield for final product (70 mg, 89%, 39% overall). LC/MSmethod A: R_(t)=3.99 min., (M+H)⁺=382.

Example 8: Synthesis of(S)-2-amino-3-phenyl-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)propanamide hydrochloride

(S)-2-amino-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide hydrochloride was prepared according to the procedure ofexample 5 from 2-amino-6-(trifluoro methoxy)benzimidazole (100 mg, 0.42mmol) and N-t-butyloxycarbonyl-L-phenylalanine (170 mg, 0.64 mmol).Yield for Boc protected intermediate 70 mg (34%). LC/MS method A:R_(t)=6.66 min., (M+H)⁺=482. Yield for final product (50 mg, 82%, 28%overall). LC/MS method A: R_(t)=3.99 min., (M+H)⁺=382.

Example 9: Synthesis of(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide

(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamidewas prepared according to the procedure of example 5 from2-amino-6-(trifluoromethoxy) benzimidazole (0.50 g, 2.1 mmol) andN-t-butyloxycarbonyl-L-azetidine-2-carboxylic acid (0.64 g, 3.2 mmol).Yield for Boc protected intermediate 0.62 g (71%). LC/MS method A:R_(t)=6.13 min., purity >95%, (M+H)⁺=418. Yield for final product (0.52g, 100%, 71% overall). LC/MS method A: R_(t)=3.66 min., purity >90%,(M+H)⁺=318.

Example 10: Synthesis of(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide

(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamidewas prepared according to the procedure of example 5 from2-amino-6-(trifluoromethoxy) benzimidazole (0.50 g, 2.1 mmol) andN-t-butyloxycarbonyl-D-azetidine-2-carboxylic acid (0.64 g, 3.2 mmol).Yield for Boc protected intermediate 0.60 g (69%). LC/MS method A:R_(t)=6.13 min., (M+H)⁺=418. Yield for final product (0.51 g, 100%, 69%overall). LC/MS method A: R_(t)=3.66 min., (M+H)⁺=318.

Example 11: Synthesis of(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamide

(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamidewas prepared according to the procedure of example 5 from2-amino-6-(trifluoromethoxy) benzimidazole (234 mg, 1.0 mmol) and(R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (300 mg, 1.3mmol). Yield for Boc protected intermediate 78 mg (17%). LC/MS method A:R_(t)=6.72 min., (M+H)⁺=446. Yield for final product (61 mg, 100%, 17%overall). LC/MS method A: R_(t)=3.78 min., (M+H)⁺=346.

Example 12: Synthesis of(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamide

(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamidewas prepared according to the procedure of example 5 from2-amino-6-(trifluoromethoxy)benzimidazole (234 mg, 1.0 mmol) and(S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (300 mg, 1.3mmol). Yield for Boc protected intermediate 78 mg (17%). LC/MS method A:R_(t)=6.72 min. (M+H)⁺=446. Yield for final product (61 mg, 100%, 17%overall). LC/MS method A: R_(t)=3.78 min., (M+H)⁺=346.

Example 13: Synthesis of2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamidewas prepared according to the procedure of example 1 from2-amino-6-(trifluoromethoxy) benzimidazole (234 mg, 1.0 mmol) andN-t-butyloxycarbonyl-2-amino-2-methylpropanamide (305 mg, 1.5 mmol).Yield for Boc protected intermediate 280 mg (67%). LC/MS method A:R_(t)=6.22 min., (M+H)⁺=420. Yield for final product (205 mg, 100%, 67%overall). LC/MS method A: R_(t)=3.68 min., (M+H)⁺=320.

Example 14: Synthesis of1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide

1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamidewas prepared according to the procedure of example 1 from2-amino-6-(trifluoromethoxy) benzimidazole (234 mg, 1.0 mmol) andN-t-butyloxycarbonyl-1-aminocyclopropanecarboxylic acid (261 mg, 1.3mmol). Yield for Boc protected intermediate 281 mg (67%). LC/MS methodA: R_(t)=6.08 min., (M+H)⁺=418. Yield for final product (227 mg, 100%,67% overall). LC/MS method A: R_(t)=3.65 min., (M+H)⁺=318.

Example 15: Synthesis of1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutanecarboxamide

1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutanecarboxamidewas prepared according to the procedure of example 1 from2-amino-6-(trifluoromethoxy) benzimidazole (234 mg, 1.0 mmol) andN-t-butyloxycarbonyl-1-aminocyclobutanecarboxylic acid (280 mg, 1.3mmol). Yield for Boc protected intermediate 281 mg (65%). LC/MS methodA: R_(t)=6.34 min., (M+H)⁺=432. Yield for final product (248 mg, 100%,65% overall). LC/MS method A: R_(t)=3.75 min., (M+H)⁺=332.

Example 16: Synthesis of2-(methylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

To a solution of 2-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide hydrochloride from example 1 above (0.40g, 1.2 mmol), N-(t-butyloxycarbonyl)sarcosine (0.28 g, 1.5 mmol) andN,N-diisopropylethylamine (0.39 g, 3.0 mmol, 0.54 ml) inN,N-dimethylformamide (10 ml) was added1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 0.57 g, 1.5 mmol) and the reactionmixture stirred for 18 hours. Ethyl acetate (100 ml) was added and themixture was washed with water (2×50 ml), 1N HCl (50 ml), saturatedsodium bicarbonate solution (50 ml) and brine (25 ml). The organicsolution was dried over sodium sulfate and evaporated to a light yellowfoamy solid which was dissolved in 4N HCl in 1,4-dioxane. The mixturestirred 2 hours and the white precipitate was filtered on a glass frit(medium), washed with 1,4-dioxane and ether and dried under vacuum toleave 344 mg (76%) of white crystalline product. LC/MS method A:R_(t)=3.62 min., (M+H)⁺=363.

Example 17: Synthesis of(S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pyrrolidine-2-carboxamide

(S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pyrrolidine-2-carboxamidewas prepared according to the procedures of example 16 from2-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidehydrochloride (60 mg, 0.25 mmol) and N-(t-butyloxycarbonyl)proline (89mg, 0.32 mmol). Yield for Boc protected intermediate 62 mg (51%). LC/MSmethod A: R_(t)=6.34 min., (M+H)⁺=432. Yield for final product (64 mg,100%, 51% overall). LC/MS method A: R_(t)=3.74 min., (M+H)⁺=389.

Example 18: Synthesis of(R)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

A solution of 2-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide hydrochloride from example 1 above (20 mg, 61μmol), N-(t-butyloxycarbonyl)-D-alanine (15 mg, 79 μmol) andN,N-Diisopropylethylamine (20 mg, 0.16 mmol, 28 μl) inN,N-dimethylformamide (0.5 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (30 mg, 79 μmol) and shaken for 18 hours. Theproduct was isolated following direct injection reverse phase HPLC(method B) and evaporation of the product fractions on a Genevacevaporator. The product weighed 23 mg (82%). The compound was dissolvedin 4N HCl/1,4-dioxane, shaken 2 hours then evaporated on a Genevacevaporator to leave the product as a white solid (20 mg, 82%) mono HClsalt. LC/MS method A: R_(t)=3.59 min., (M+H)⁺=363. The followingcompounds were prepared using the same method and scale as example 18.

Example 19: Synthesis of3-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

3-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamidewas prepared according to the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-(t-butyloxycarbonyl)-β-alanine (15 mg, 79 μmol). Yield=5.5 mg (23%).LC/MS method A: R_(t)=3.57 min., (M+H)⁺=363.

Example 20: Synthesis of1-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclopropane-1-carboxamide

1-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclopropane-1-carboxamide was prepared according to the procedure of example18 from 2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-1-(t-butyloxycarbonyl)aminocyclopropane-1-carboxylic acid (16 mg, 79μmol). Yield=20 mg (80%). LC/MS method A: R_(t)=3.60 min., (M+H)⁺=375.

Example 21: Synthesis of(S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)azetidine-2-carboxamide

(S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)azetidine-2-carboxamidewas prepared according to the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) and(S)—N-(t-butyloxycarbonyl)azetidine-2-carboxylic acid (16 mg, 79 μmol).Yield=20 mg (80%). LC/MS method A: R_(t)=3.62 min., (M+H)⁺=375.

Example 22: Synthesis of2-amino-2-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

2-amino-2-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide was prepared according to the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-(t-butyloxycarbonyl)aminoisobutyric acid (16 mg, 79 μmol). Yield=20 mg(80%). LC/MS method A: R_(t)=3.63 min., (M+H)⁺=377.

Example 23: Synthesis of(S)-2-(methylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

(S)-2-(methylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide was prepared according to the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-(t-butyloxycarbonyl)-N-methyl-L-alanine (16 mg, 79 μmol). Yield=20 mg(80%). LC/MS method A: R_(t)=3.64 min., (M+H)⁺=377.

Example 24: Synthesis of(R)-2-(methylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

(R)-2-(methylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide was prepared according to the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-(t-butyloxycarbonyl)-N-methyl-D-alanine (16 mg, 79 μmol). Yield=18 mg(72%). LC/MS method A: R_(t)=3.64 min., (M+H)⁺=377.

Example 25: Synthesis of(R)-2-amino-3-hydroxy-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

(R)-2-amino-3-hydroxy-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide was prepared according to the procedure of example 18from 2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-(t-butyloxycarbonyl)-D-serine (16 mg, 79 μmol). Yield=16 mg (63%).LC/MS method A: R_(t)=3.50 min., (M+H)⁺=379.

Example 26: Synthesis of(R)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pent-4-ynamide

(R)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pent-4-ynamide was prepared accordingto the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-(t-butyloxycarbonyl)-(R)-2-amino-4-pentynyl carboxylic acid (17 mg, 79μmol). Yield=22 mg (85%). LC/MS method A: R_(t)=3.71 min., (M+H)⁺=387.

Example 27: Synthesis of (S)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pent-4-ynamide

(S)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pent-4-ynamide was prepared accordingto the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-(t-butyloxycarbonyl)-(S)-2-amino-4-pentynyl carboxylic acid (17 mg, 79μmol). Yield=22 mg (85%). LC/MS method A: R_(t)=3.71 min., (M+H)⁺=387.

Example 28: Synthesis of (R)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pyrrolidine-2-carboxamide

(R)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pyrrolidine-2-carboxamide was preparedaccording to the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-(t-butyloxycarbonyl)-D-proline (17 mg, 79 μmol). Yield=21 mg (81%).LC/MS method A: R_(t)=3.70 min., (M+H)⁺=389.

Example 29: Synthesis of 1-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclobutane-1-carboxamide

1-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclobutane-1-carboxamidewas prepared according to the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) and1-(N-(t-butyloxycarbonyl)amino) cyclobutanecarboxylic acid (17 mg, 79μmol). Yield=1.5 mg (5.8%). LC/MS method A: R_(t)=3.69 min., (M+H)⁺=389.

Example 30: Synthesis of (S)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pentanamide

(S)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl) pentanamide was prepared according tothe procedure of example 18 from 2-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide hydrochloride from example 1 above (20 mg, 61μmol) and (S)-2-(N-(t-butyloxycarbonyl)amino)pentanoic acid (17 mg, 79μmol). Yield=19 mg (73%). LC/MS method A: R_(t)=3.88 min., (M+H)⁺=391.

Example 31: Synthesis of (R)-2-amino-3-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)butanamide

(R)-2-amino-3-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)butanamide was prepared according to the procedure of example 18from 2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) and(R)-2-(N-(t-butyloxycarbonyl)valine (17 mg, 79 μmol). Yield=21 mg (81%).LC/MS method A: R_(t)=3.83 min., (M+H)⁺=391.

Example 32: Synthesis of(S)-4-oxo-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pyrrolidine-2-carboxamide

(S)-4-oxo-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pyrrolidine-2-carboxamide was prepared according to the procedure ofexample 18 from 2-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide hydrochloride from example 1 above (20 mg, 61μmol) and (S)—N-t-butyloxycarbonyl-4-oxopyrrolidine-2-carboxylic acid(18 mg, 79 μmol). Yield=16 mg (60%). LC/MS method A: R_(t)=3.64 min.,(M+H)⁺=403.

Example 33: (S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)piperidine-2-carboxamide

(S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)piperidine-2-carboxamide was prepared accordingto the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) and(S)—N-t-butyloxycarbonylpiperidine-2-carboxylic acid (18 mg, 79 μmol).Yield=20 mg (75%). LC/MS method A: R_(t)=3.73 min., (M+H)⁺=403.

Example 34: Synthesis of (S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)morpholine-3-carboxamide

(S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)morpholine-3-carboxamide was prepared accordingto the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) and(S)—N-t-butyloxycarbonylmorpholine-2-carboxylic acid (18 mg, 79 μmol).Yield=24 mg (89%). LC/MS method A: R_(t)=3.64 min., (M+H)⁺=405.

Example 35: Synthesis of (R)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)morpholine-3-carboxamide

(R)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)morpholine-3-carboxamide was prepared accordingto the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) and(R)—N-t-butyloxycarbonylmorpholine-2-carboxylic acid (18 mg, 79 μmol).Yield=25 mg (93%). LC/MS method A: R_(t)=3.64 min., (M+H)⁺=405.

Example 36: Synthesis of (R)-2-amino-4-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pentanamide

(R)-2-amino-4-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pentanamide was prepared according to the procedure of example 18from 2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-t-butyloxycarbonyl-D-leucine (18 mg, 79 μmol). Yield=21 mg (78%).LC/MS method A: R_(t)=4.01 min., (M+H)⁺=405.

Example 37: Synthesis of(R)-4-oxo-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)piperidine-2-carboxamide

(R)-4-oxo-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)piperidine-2-carboxamide was preparedaccording to the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) and(R)—N-t-butyloxycarbonyl-4-oxopiperidine-2-carboxylic acid (19 mg, 79μmol). Yield=15 mg (54%). LC/MS method A: R_(t)=3.68 min., (M+H)⁺=417.

Example 38: Synthesis of4-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)tetrahydro-2H-pyran-4-carboxamide

4-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)tetrahydro-2H-pyran-4-carboxamide was preparedaccording to the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) and4-N-t-butyloxycarbonylamino-2,3,5,6-tetrahydropyran-4H-4-carboxylic acid(19 mg, 79 μmol). Yield=24 mg (87%). LC/MS method A: R_(t)=3.63 min.,(M+H)⁺=419.

Example 39: (R)-2-amino-N1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pentanediamide

(R)-2-amino-N1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl) pentanediamide: was prepared accordingto the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-t-butyloxycarbonyl-D-glutamine (20 mg, 79 μmol). Yield=24 mg (72%).LC/MS method A: R_(t)=3.47 min., (M+H)⁺=420.

Example 40: (R)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy) benzo[d]thiazol-2-yl)amino)ethyl)-3-phenylpropanamide

(R)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)-3-phenylpropanamide was preparedaccording to the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-t-butyloxycarbonyl-D-phenylalanine (21 mg, 79 μmol). Yield=22 mg(76%). LC/MS method A: R_(t)=4.11 min., (M+H)⁺=439.

Example 41: (R)-2-amino-3-cyclohexyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d] thiazol-2-yl)amino)ethyl)propanamide

(R)-2-amino-3-cyclohexyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide was prepared according to the procedure of example 18from 2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-t-butyloxycarbonyl-D-cyclohexyl alanine (21 mg, 79 μmol). Yield=15 mg(51%). LC/MS method A: R_(t)=4.43 min., (M+H)⁺=445.

Example 42: Synthesis of(R)-2-amino-3-(benzyloxy)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

(R)-2-amino-3-(benzyloxy)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide was prepared according to the procedure ofexample 18 from 2-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide hydrochloride from example 1 above (20 mg, 61μmol) and N-t-butyloxycarbonyl-O-benzyl-D-serine (23 mg, 79 μmol).Yield=25 mg (81%). LC/MS method A: R_(t)=4.30 min., (M+H)⁺=469.

Example 43: Synthesis of(S)-2-amino-3-(benzyloxy)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

(S)-2-amino-3-(benzyloxy)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide was prepared according to the procedure ofexample 18 from 2-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide hydrochloride from example 1 above (20 mg, 61μmol) and N-t-butyloxycarbonyl-O-benzyl-L-serine (23 mg, 79 μmol).Yield=26 mg (84%). LC/MS method A: R_(t)=4.30 min., (M+H)⁺=469.

Example 44: Synthesis of(R)-2-amino-3-(1H-indol-3-yl)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

(R)-2-amino-3-(1H-indol-3-yl)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamidewas prepared according to the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) andN-t-butyloxycarbonyl-L-tryptophan (24 mg, 79 μmol). Yield=22 mg (70%).

Example 45: Synthesis of (2S,4R)-4-(benzyloxy)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pyrrolidine-2-carboxamide

(2S,4R)-4-(benzyloxy)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pyrrolidine-2-carboxamide was prepared according to the procedureof example 18 from 2-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide hydrochloride from example 1 above (20 mg, 61μmol) and tert-butyl(2S,4R)-4-(benzyloxy)-2-carbamoylpyrrolidine-1-carboxylate (25 mg, 79μmol). Yield=24 mg (74%). LC/MS method A: R_(t)=4.13 min., (M+H)⁺=495.

Example 46: Synthesis of (S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)piperazine-2-carboxamide

(S)—N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)piperazine-2-carboxamide was prepared accordingto the procedure of example 18 from2-amino-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)acetamidehydrochloride from example 1 above (20 mg, 61 μmol) and(S)—N,N′-di-(tert-butyloxycarbonyl) morpholine-2-carboxylic acid (26 mg,79 μmol). Yield=23 mg (70%). LC/MS method A: R_(t)=3.23 min.,(M+H)⁺=404.

Example 47: Synthesis of(R)-2-amino-4-(benzyloxy)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)butanamide

(R)-2-amino-4-(benzyloxy)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)butanamide was prepared according to the procedure ofexample 18 from 2-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide hydrochloride from example 1 above (20 mg, 61μmol) and N-t-butyloxycarbonyl-O-benzyl-D-homoserine (27 mg, 79 μmol).Yield=26 mg (77%). LC/MS method A: R_(t)=4.39 min (M+H)⁺=482.

Example 48: Synthesis of(R)-1-(N,N-dimethyl-L-valyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

A solution of(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidefrom example 6 above (0.11 g, 0.30 mmol), N,N-dimethyl-L-valine (52 mg,0.36 mmol) and N,N-diisopropylethylamine (46 mg, 0.36 mmol, 65 μl) inN,N-dimethylformamide (2 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (137 mg, 0.36 mmol) and stirred 72 hours. Theproduct was purified by reverse phase HPLC (method B, direct injectionof the reaction mixture). The product fractions were combined andevaporated on a Genevac evaporator to leave the mono TFA salt product asa white powder (31 mg, 18%). LC/MS method A: R_(t)=4.06 min.,(M+H)⁺=459.

Example 49: Synthesis of(R)-1-(L-valyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

A solution of(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidefrom example 6 above (25 mg, 0.68 μmol), N-t-butyloxycarbonyl-L-valine(18 mg, 81 μmol) and N,N-diisopropylethylamine (10 μmol, 18 μl) inN,N-dimethylformamide (0.3 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (39 mg, 10 μmol) and stirred 72 hours. Theproduct was purified by reverse phase HPLC (method B, direct injectionof the reaction mixture). The product fractions were combined andevaporated on a Genevac evaporator to leave the product as a whitepowder which was stirred for 2 hours in 4N HCl/1,4-dioxane (2 ml). Thesolvents were evaporated to leave the product as a white solid (27 mg,85% two steps). LC/MS method A: R_(t)=4.23 min., (M+H)⁺=431.02.

Example 50: Synthesis of(R)-1-D-valyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(R)-1-D-valyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide was prepared according to the procedure ofexample 49 from(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(37 mg, 0.1 mmol) and N-t-butyloxycarbonyl-D-valine (26 mg, 0.13 mmol).Yield=35 mg, 75% two steps. LC/MS method A: R_(t)=4.24 min.,(M+H)⁺=431.02.

Example 51: Synthesis of(R)-1-glycinyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(R)-1-glycinyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide was prepared according to the procedure ofexample 49 from (R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide (37 mg, 0.1 mmol) andN-t-butyloxycarbonylglycine (25 mg, 0.13 mmol). Yield=42 mg, 100% twosteps. LC/MS method A: R_(t)=3.78 min., (M+H)⁺=388.94.

Example 52:(R)-1-N-ethylglycinyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(R)-1-N-ethylglycinyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide (74 mg, 0.2 mmol) and N-Boc-N-ethyl glycine(61 mg, 0.30 mmol) Yield=88 mg, 97% two steps. LC/MS method A:R_(t)=3.94 min., (M+H)⁺=417.02.

Example 53: Synthesis of(R)-1-N-isopropylglycinyl-N-(6-(trifluoromethoxy) benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(R)-1-N-isopropylglycinyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide (74 mg, 0.2 mmol) andN-t-butyloxycarbonyl-N-isopropyl glycine (65 mg, 0.30 mmol). Yield=98mg, 100% two steps. LC/MS method A: R_(t)=4.03 min., (M+H)⁺=431.09.

Example 54: Synthesis of (R)-1-N-t-butylglycinyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(R)-1-N-t-butylglycinyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide was prepared according tothe procedure of example 49 from(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(74 mg, 0.2 mmol) and N-t-butyloxycarbonyl-N-tert-butyl glycine (69 mg,0.30 mmol). Yield=86 mg, 89% two steps. LC/MS method A: R_(t)=4.13 min.,(M+H)⁺=445.10.

Example 55: Synthesis of(R)-1-(3-amino-2,2-dimethylpropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(R)-1-(3-amino-2,2-dimethylpropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(R)—N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)pyrrolidine-2-carboxamide (37 mg, 0.1 mmol) andN-t-butyloxycarbonyl-3-amino-2,2-dimethylpropanoic acid (29 mg, 0.13mmol). Yield=53 mg, 100% two steps. LC/MS method A: R_(t)=4.01 min.,(M+H)⁺=431.02.

Example 56: Synthesis of(R)-1-(1-(aminomethyl)cyclopropane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(R)-1-(1-(aminomethyl)cyclopropane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide was prepared according to theprocedure of example 49 from(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(74 mg, 0.2 mmol) and N-t-butyloxycarbonyl-1-(aminomethyl)cyclopropanecarboxylic acid (56 mg, 0.26 mmol). Yield=93 mg, 100% two steps. LC/MSmethod A: R_(t)=3.92 min., (M+H)⁺=429.05.

Example 57: Synthesis of(R)-1-(1-(aminomethyl)cyclopentane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(R)-1-(1-(aminomethyl)cyclopentane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(74 mg, 0.2 mmol) and N-t-butyloxycarbonyl-1-(aminomethyl)cyclopentanecarboxylic acid (63 mg, 0.26 mmol). Yield=91 mg, 92% two steps. LC/MSmethod A: R_(t)=4.21 min., (M+H)⁺=457.13.

Example 58: Synthesis of(R)-1-(1-(aminomethyl)cyclohexane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(R)-1-(1-(aminomethyl)cyclohexane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(37 mg, 0.1 mmol) and N-t-butyloxycarbonyl-1-(aminomethyl)cyclohexanecarboxylic acid (33 mg, 0.13 mmol). Yield=28 mg, 55% two steps. LC/MSmethod A: R_(t)=4.54 min., (M+H)⁺=471.08.

Example 59: Synthesis of(S)-1-(3-amino-2,2-dimethylpropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-(3-amino-2,2-dimethylpropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide was prepared according to the procedure ofexample 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(37 mg, 0.1 mmol) and N-t-butyloxycarbonyl-2-amino-2,2-dimethylpropanecarboxylic acid (29 mg, 0.13 mmol). Yield=45 mg, 96% two steps. LC/MSmethod A: R_(t)=4.03 min., (M+H)⁺=431.02.

Example 60: Synthesis of(S)-1-(1-(aminomethyl)cyclopropane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-(1-(aminomethyl)cyclopropane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide was prepared according to theprocedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(37 mg, 0.1 μmol) and N-t-butyloxycarbonyl-1-(aminomethyl)cyclopropanecarboxylic acid (29 mg, 0.13 μmol). Yield=42 mg, 90% two steps. LC/MSmethod A: R_(t)=3.94 min., (M+H)⁺=428.98.

Example 61: Synthesis of(S)-1-(1-(aminomethyl)cyclopentane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-(1-(aminomethyl)cyclopentane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(37 mg, 0.1 μmol) and N-t-butyloxycarbonyl-1-(aminomethyl)cyclopentanecarboxylic acid (29 mg, 0.13 μmol). Yield=33 mg, 67% two steps. LC/MSmethod A: R_(t)=4.21 min., (M+H)⁺=457.07.

Example 62:(S)-1-(D-valyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-(D-valyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide (25 mg, 68 μmol) andN-t-butyloxycarbonyl-D-valine (18 mg, 82 μmol). Yield=33 mg (48%, twosteps). LC/MS method A: R_(t)=4.23 min., (M+H)⁺=431.13.

Example 63: Synthesis of(S)-1-(L-valyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-(L-valyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide (37 mg, 0.1 μmol) andN-(t-butyloxycarbonyl)valine (24 mg, 0.12 μmol). Yield=35 mg (75%, twosteps). LC/MS method A: R_(t)=4.23 min., (M+H)⁺=431.02.

Example 64: Synthesis of(S)-1-glycyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-glycyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide (37 mg, 0.1 μmol) andN-(t-butyloxycarbonyl)glycine (21 mg, 0.12 μmol). Yield=45 mg (100%, twosteps). LC/MS method A: R_(t)=3.78 min., (M+H)⁺=388.94.

Example 65: Synthesis of(S)-1-(D-alanyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-(D-alanyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide (37 mg, 0.1 μmol) andN-(t-butyloxycarbonyl)-D-alanine (23 mg, 0.12 μmol). Yield=55 mg (100%,two steps). LC/MS method A: R_(t)=3.82 min., (M+H)⁺=403.01.

Example 66: Synthesis of(S)-1-(methylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-(methylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(37 mg, 0.1 mmol) and N-(t-butyloxycarbonyl)sarcosine (23 mg, 0.12mmol). Yield=31 mg (71%, two steps). LC/MS method A: R_(t)=3.85 min.,(M+H)⁺=403.01.

Example 67: Synthesis of(S)-1-(ethylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-(ethylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(37 mg, 0.1 mmol) and N-(t-butyloxycarbonyl)-N-ethylglycine (24 mg, 0.12mmol). Yield=35 mg (65%, two steps). LC/MS method A: R_(t)=3.94 min.,(M+H)⁺=416.95.

Example 68: Synthesis of(S)-1-(isopropylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-(isopropylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(37 mg, 0.1 mmol) and N-(t-butyloxy carbonyl)-N-isopropylglyeine (26 mg,0.12 mmol). Yield=43 mg (79%, two steps). LC/MS method A: R_(t)=4.06min., (M+H)⁺=431.02.

Example 69: Synthesis of(S)-1-(tert-butylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-(tert-butylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(65 mg, 0.18 mmol) and N-(t-butyloxy carbonyl)-N-t-butylglyeine (61 mg,0.26 mmol). Yield=62 mg (73%, two steps). LC/MS method A: R_(t)=4.16min., (M+H)⁺=445.10.

Example 70: Synthesis of(S)-1-(D-leucyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-(D-leucyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide:was prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide (37 mg, 0.1 mmol) andN-(t-butyloxycarbonyl)-D-leucine (26 mg, 0.12 mmol). Yield=33 mg (69%,two steps). LC/MS method A: R_(t)=4.18 min., (M+H)⁺=445.03.

Example 71: Synthesis of(S)-1-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

(S)-1-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)pyrrolidine-2-carboxamide (37 mg, 0.1 mmol) andN-t-butyloxycarbonyl-beta-alanine (23 mg, 0.12 mmol). Yield=46 mg (100%,two steps). LC/MS method A: R_(t)=3.64 min., (M+H)⁺=403.01.

Example 72: Synthesis of(S)-1-glycyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide

(S)-1-glycyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)azetidine-2-carboxamide(37 mg, 0.1 mmol) and N-t-butyloxycarbonylglycine (26 mg, 0.13 mmol).Yield=21 mg (43%, two steps). LC/MS method A: R_(t)=3.69 min.,(M+H)⁺=374.94.

Example 73: Synthesis of(S)-1-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide

(S)-1-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide(37 mg, 0.1 mmol) and N-t-butyloxycarbonyl-beta-alanine (29 mg, 0.13mmol). Yield=18 mg (36%, two steps). LC/MS method A: R_(t)=3.76 min.,(M+H)⁺=388.94.

Example 74: Synthesis of(S)-1-(1-(aminomethyl)cyclopropane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide

(S)-1-(1-(aminomethyl)cyclopropane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide was prepared according to theprocedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamideTFA salt (46 mg, 0.1 mmol) andN-t-butyloxycarbonyl-1-(aminomethyl)cyclopropane carboxylic acid (29 mg,0.13 mmol). Yield=49 mg (93%, two steps). LC/MS method A: R_(t)=3.90min., (M+H)⁺=414.98.

Example 75: Synthesis of(S)-1-(1-(aminomethyl)cyclopentane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamide

(S)-1-(1-(aminomethyl)cyclopentane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)azetidine-2-carboxamideTFA salt (46 mg, 0.1 mmol) andN-t-butyloxycarbonyl-1-(aminomethyl)cyclopentane carboxylic acid (29 mg,0.13 mmol). Yield=49 mg (88%, two steps). LC/MS method A: R_(t)=4.16min., (M+H)⁺=443.06.

Example 76: Synthesis of(S)-1-glycyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamide

(S)-1-glycyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclohexane-2-carboxamide hydrochloride (41 mg, 0.10 mmol)and N-t-butyloxycarbonylglycine (26 mg, 0.13 mmol). Yield=43 mg (98%,two steps). LC/MS method A: R_(t)=4.08 min., (M+H)⁺=402.94.

Example 77: Synthesis of(S)-1-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamide

(S)-1-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamidewas prepared according to the procedure of example 49 from(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclohexane-2-carboxamidehydrochloride (41 mg, 0.10 mmol) and N-t-butyloxycarbonyl-beta-alanine(29 mg, 0.13 mmol). Yield=42 mg (98%, two steps). LC/MS method A:R_(t)=4.15 min., (M+H)⁺=416.95.

Example 78: Synthesis of(S)-1-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzothiazol-2-yl)piperidine-2-carboxamide

(R)-1-glycyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamidewas prepared according to the procedure of example 49 from(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclohexane-2-carboxamide hydrochloride (30 mg, 0.073 mmol)and N-t-butyloxycarbonylglycine (17 mg, 0.098 mmol). Yield=18 mg (55%,two steps). LC/MS method A: R_(t)=4.17 min., (M+H)⁺=402.94.

Example 79: Synthesis of(R)-1-(methylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamide

(R)-1-(methylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)piperidine-2-carboxamidewas prepared according to the procedure of example 49 from(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclohexane-2-carboxamidehydrochloride (30 mg, 0.073 mmol) and N-t-butyloxycarbonylglycine (18mg, 0.098 mmol). Yield=28 mg (82%, two steps). LC/MS method A:R_(t)=4.25 min., (M+H)⁺=416.95.

Example 80: Synthesis of1-(2-aminoacetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide

1-(2-aminoacetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamidewas prepared according to the procedure of example 49 from1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide hydrochloride (36 mg, 0.10 mmol)and N-t-butyloxycarbonylglycine (23 mg, 0.13 mmol). Yield=35 mg (85%,two steps). LC/MS method A: R_(t)=3.90 min., (M+H)⁺=375.01.

Example 81: Synthesis of1-(2-(methylamino)acetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide

1-(2-(methylamino)acetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamidewas prepared according to the procedure of example 49 from1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamidehydrochloride (36 mg, 0.10 mmol) and N-t-butyloxycarbonyl-N-methylglycine (25 mg, 0.13 mmol). Yield=28 mg (66%, two steps). LC/MS methodA: R_(t)=3.94 min., (M+H)⁺=389.01.

Example 82: Synthesis of1-(2-aminoacetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide

1-(2-aminoacetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamidewas prepared according to the procedure of example 49 from1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutanecarboxamide hydrochloride (33 mg, 0.10 mmol) andN-t-butyloxycarbonylglycine (23 mg, 0.13 mmol). Yield=36 mg (85%, twosteps). LC/MS method A: R_(t)=4.06 min., (M+H)⁺=388.94.

Example 83: Synthesis of1-(2-(methylamino)acetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide

1-(2-(methylamino)acetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamidewas prepared according to the procedure of example 49 from1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutanecarboxamide hydrochloride (33 mg, 0.10 mmol) andN-t-butyloxycarbonyl-N-methylglycine (25 mg, 0.13 mmol). Yield=22 mg(50%, two steps). LC/MS method A: R_(t)=4.13 min., (M+H)⁺=403.01.

Example 84: Synthesis of1-(3-amino-2,2-dimethylpropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide

1-(3-amino-2,2-dimethylpropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamidewas prepared according to the procedure of example 49 from1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutanecarboxamidehydrochloride (37 mg, 0.10 mmol) andN-t-butyloxycarbonyl-2,2-dimethyl-beta-alanine (30 mg, 0.15 mmol).Yield=30 mg (55%, two steps). LC/MS method A: R_(t)=4.20 min.,(M+H)⁺=431.16.

Example 85: Synthesis of1-(aminomethyl)-N-(1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)cyclopentane-1-carboxamide

1-(aminomethyl)-N-(1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)cyclopentane-1-carboxamide was prepared according to the procedure ofexample 49 from1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutanecarboxamidehydrochloride (37 mg, 0.10 mmol) andN-t-butyloxycarbonyl-1-(aminomethyl)cyclopentane carboxylic acid (33 mg,0.15 mmol). Yield=23 mg (47%, two steps). LC/MS method A: R_(t)=4.40min., (M+H)⁺=457.13.

Example 86: Synthesis of1-(2-(isopropylamino)acetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide

1-(2-(isopropylamino)acetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide was prepared according to the procedure of example49 from1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutanecarboxamidehydrochloride (37 mg, 0.10 mmol) andN-t-butyloxycarbonyl-N-isopropylglycine (30 mg, 0.15 mmol). Yield=30 mg(64%, two steps). LC/MS method A: R_(t)=4.31 min., (M+H)⁺=431.16.

Example 87: Synthesis of1-(2-(isopropylamino)acetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide

1-(1-(aminomethyl)cyclopropane-1-carboxamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide was prepared according to theprocedure of example 49 from1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutanecarboxamidehydrochloride (55 mg, 0.15 mmol) andN-t-butyloxycarbonyl-1-(aminomethyl)cyclopropane carboxylic acid (48 mg,0.22 mmol). Yield=48 mg (69%, two steps). LC/MS method A: R_(t)=4.19min., (M+H)⁺=429.19.

Example 88: Synthesis of1-(aminomethyl)-N-(1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)cyclohexane-1-carboxamide

1-(aminomethyl)-N-(1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)cyclobutyl)cyclohexane-1-carboxamide was prepared according to the procedure ofexample 49 from 1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutanecarboxamide hydrochloride (55 mg, 0.15 mmol)and N-t-butyloxycarbonyl-1-(aminomethyl)cyclohexane carboxylic acid (58mg, 0.22 mmol). Yield=43 mg (57%, two steps). LC/MS method A: R_(t)=4.50min., (M+H)⁺=471.21.

Example 89: Synthesis of(R)-1-(2-aminopropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide

(R)-1-(2-aminopropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamidewas prepared according to the procedure of example 49 from1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutanecarboxamidehydrochloride (55 mg, 0.15 mmol) and N-t-butyloxycarbonyl-D-alanine (42mg, 0.22 mmol). Yield=27 mg (41%, two steps). LC/MS method A: R_(t)=4.10min., (M+H)⁺=403.15.

Example 90: Synthesis of(R)-1-(2-amino-3-methylbutanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide

(R)-1-(2-amino-3-methylbutanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamidewas prepared according to the method of example 49 from1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutanecarboxamidehydrochloride (55 mg, 0.15 mmol) and N-t-butyloxycarbonyl-D-valine (49mg, 0.22 mmol). Yield=57 mg (81%, two steps). LC/MS method A: R_(t)=4.32min., (M+H)⁺=431.16.

Example 91: Synthesis of(S)-2-(2-aminoacetamido)-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

(S)-2-(2-aminoacetamido)-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamidewas prepared according to the procedure of example 49 from(S)-2-amino-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide (19 mg, 0.05 mmol) andN-t-butyloxycarbonylglycine (13 mg, 0.065 mmol). Yield=20 mg (84%, twosteps). LC/MS method A: R_(t)=4.36 min., (M+H)⁺=438.98.

Example 92: Synthesis of(S)-2-(2-(methylamino)acetamido)-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

(S)-2-(2-(methylamino)acetamido)-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamidewas prepared according to the procedure of example 49 from(S)-2-amino-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(19 mg, 0.05 mmol) and N-t-butyloxycarbonyl-N-methylglycine (14 mg,0.065 mmol). Yield=13 mg (53%, two steps). LC/MS method A: R_(t)=4.41min., (M+H)⁺=453.05.

Example 92: Synthesis of(S)-2-((R)-2-aminopropanamido)-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

(S)-2-((R)-2-aminopropanamido)-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamidewas prepared according to the procedure of example 49 from(S)-2-amino-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide (42 mg, 0.10 mmol) andN-t-butyloxycarbonyl-D-alanine (28 mg, 0.15 mmol). Yield=43 mg (88%, twosteps). LC/MS method A: R_(t)=4.32 min., (M−14+H)⁺=438.98.

Example 93: Synthesis of(S)-2-((S)-2-aminopropanamido)-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

(S)-2-((S)-2-aminopropanamido)-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamidewas prepared according to the procedure of example 49 from(S)-2-amino-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide (42 mg, 0.10 mmol) andN-t-butyloxycarbonyl-L-alanine (28 mg, 0.15 mmol). Yield=43 mg (88%, twosteps). LC/MS method A: R_(t)=4.32 min., (M−14+H)⁺=438.98.

Example 94: Synthesis of(R)-2-amino-3-methyl-N—((S)-1-oxo-3-phenyl-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)butanamide

(R)-2-amino-3-methyl-N—((S)-1-oxo-3-phenyl-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)butanamidewas prepared according to the procedure of example 49 from(S)-2-amino-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(42 mg, 0.10 mmol) and N-t-butyloxycarbonyl-D-valine (33 mg, 0.15 mmol).Yield=46 mg (89%, two steps). LC/MS method A: R_(t)=3.62 min.,(M−14+H)⁺=467.06.

Example 95: Synthesis of(S)-2-amino-2-methyl-N-(1-oxo-3-phenyl-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamide

(S)-2-amino-2-methyl-N-(1-oxo-3-phenyl-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamidewas prepared according to the procedure of example 49 from(S)-2-amino-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(42 mg, 0.10 mmol) and N-t-butyloxycarbonylsarcosine (33 mg, 0.15 mmol).Yield=52 mg (100%, two steps). LC/MS method A: R_(t)=4.38 min.,(M−14+H)⁺=452.99.

Example 96: Synthesis of(S)-1-amino-N-(1-oxo-3-phenyl-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclopropane-1-carboxamide

(S)-1-amino-N-(1-oxo-3-phenyl-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclopropane-1-carboxamidewas prepared according to the procedure of example 49 from(S)-2-amino-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(42 mg, 0.10 mmol) and 1-N-t-butyloxycarbonylaminocyclopropanecarboxylic acid (30 mg, 0.15 mmol). Yield=41 mg (82%, two steps). LC/MSmethod A: R_(t)=4.33 min., (M−14+H)⁺=451.01.

Example 97: Synthesis of(S)-1-amino-N-(1-oxo-3-phenyl-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclobutane-1-carboxamide

(S)-1-amino-N-(1-oxo-3-phenyl-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclobutane-1-carboxamide was prepared according to theprocedure of example 49 from(S)-2-amino-3-phenyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(42 mg, 0.10 mmol) and1-(N-t-butyloxycarbonylamino)cyclobutanecarboxylic acid (32 mg, 0.15mmol). Yield=41 mg (80%, two steps). LC/MS method A: R_(t)=4.43 min.,(M−14+H)⁺=465.16.

Example 98: Synthesis of1-(3-amino-2,2-dimethylpropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide

1-(3-amino-2,2-dimethylpropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamidewas prepared according to the procedure of example 49 from1-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide(42 mg, 0.10 mmol) and3-((N-t-butyloxycarbonyl)amino)-2,2-dimethylpropanoic acid (32 mg, 0.15mmol). Yield=41 mg (80%, two steps). LC/MS method A: R_(t)=4.43 min.,(M−14+H)⁺=465.16.

Example 99: Synthesis of(R)-2-(2-aminopropanamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

(R)-2-(2-aminopropanamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamidewas prepared according to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide (50 mg, 0.14 mmol) andN-t-butyloxycarbonyl-D-alanine (40 mg, 0.21 mmol). Yield=35 mg (59%, twosteps). LC/MS method A: R_(t)=3.99 min., (M+H)⁺=390.98.

Example 100: Synthesis of(S)-2-(2-aminopropanamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

(S)-2-(2-aminopropanamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamidewas prepared according to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(50 mg, 0.14 mmol) and N-(t-butyloxycarbonyl)alanine (40 mg, 0.21 mmol).Yield=36 mg (60%, two steps). LC/MS method A: R_(t)=4.00 min.,(M+H)⁺=390.98.

Example 101: Synthesis of 2-(2-aminoacetamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

2-(2-aminoacetamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamidewas prepared according to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide (50 mg, 0.14 mmol) andN-(t-butyloxycarbonyl)glycine (37 mg, 0.21 mmol). Yield=40 mg (69%, twosteps). LC/MS method A: R_(t)=3.93 min., (M+H)⁺=376.91.

Example 102: Synthesis of(R)-2-amino-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)-3-phenylpropanamide

(R)-2-amino-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)-3-phenylpropanamide was prepared according to the procedureof example 49 from 2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide (36 mg, 0.10 mmol) andN-(t-butyloxycarbonyl)-D-phenylalanine (34 mg, 0.13 mmol). Yield=24 mg(49%, two steps). LC/MS method A: R_(t)=4.62 min., (M+H)⁺=467.13.

Example 103: Synthesis of(S)-2-amino-3-(benzyloxy)-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamide

(S)-2-amino-3-(benzyloxy)-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamidewas prepared according to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(36 mg, 0.10 mmol) and(S)-2-(N-t-butyloxycarbonyl)amino-3-(benzyloxy)propanoic acid (38 mg,0.13 mmol). Yield=51 mg (95%, two steps). LC/MS method A: R_(t)=4.76min., (M+H)⁺=497.13.

Example 104: Synthesis of1-amino-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclopropane-1-carboxamide

1-amino-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclopropane-1-carboxamidewas prepared according to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide (53 mg, 0.15 mmol) and1-N-(t-butyloxycarbonyl)aminocyclopropanecarboxylic acid (40 mg, 0.19mmol). Yield=41 mg (62%, two steps). LC/MS method A: R_(t)=4.03 min.,(M+H)⁺=403.01.

Example 105: Synthesis of1-amino-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclobutane-1-carboxamide

1-amino-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclobutane-1-carboxamidewas prepared according to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide (53 mg, 0.15 mmol) and1-N-(t-butyloxycarbonyl)aminocyclobutanecarboxylic acid (41 mg, 0.19mmol). Yield=37 mg (54%, two steps). LC/MS method A: R_(t)=4.13 min.,(M+H)⁺=417.15.

Example 106: Synthesis of2-amino-2-methyl-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamide

2-amino-2-methyl-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamidewas prepared according to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(53 mg, 0.15 mmol) and 2-N-(t-butyloxycarbonyl)amino-2-methylpropanoicacid (40 mg, 0.19 mmol). Yield=10 mg (15%, two steps). LC/MS method A:R_(t)=4.02 min., (M+H)⁺=405.05.

Example 107: Synthesis of3-amino-2,2-dimethyl-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamide

3-amino-2,2-dimethyl-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamidewas prepared according to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(53 mg, 0.15 mmol) and3-N-(t-butyloxycarbonyl)amino-2,2-dimethylpropanoic acid (40 mg, 0.18mmol). Yield=5.8 mg (8.5%, two steps). LC/MS method A: R_(t)=4.06 min.,(M+H)⁺=419.12.

Example 108: Synthesis of1-(aminomethyl)-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclopropane-1-carboxamide

1-(aminomethyl)-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclopropane-1-carboxamidewas prepared according to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(53 mg, 0.15 mmol) and1-((N-t-butyloxycarbonylamino)methyl)cyclopropanecarboxylic acid (39 mg,0.18 mmol). Yield=20 mg (29%, two steps). LC/MS method A: R_(t)=4.05min., (M+H)⁺=417.09.

Example 109: Synthesis of1-(aminomethyl)-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclopentane-1-carboxamide

1-(aminomethyl)-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclopentane-1-carboxamide was prepared according to theprocedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(53 mg, 0.15 mmol) and1-((N-t-butyloxycarbonylamino)methyl)cyclopentanecarboxylic acid (44 mg,0.18 mmol). Yield=8.0 mg (11%, two steps). LC/MS method A: R_(t)=4.24min., (M+H)⁺=445.17.

Example 110: Synthesis of1-(aminomethyl)-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclohexane-1-carboxamide

1-(aminomethyl)-N-(2-methyl-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)cyclohexane-1-carboxamide was prepared according to theprocedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(53 mg, 0.15 mmol) and1-((N-t-butyloxycarbonyl)aminomethyl)cyclohexanecarboxylic acid (44 mg,0.18 mmol). Yield=8.0 mg (11%, two steps). LC/MS method A: R_(t)=3.26min., (M+H)⁺=459.24.

Example 111: Synthesis of2-methyl-2-(2-(methylamino)acetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

2-methyl-2-(2-(methylamino)acetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamidewas prepared according to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(53 mg, 0.15 mmol) and N-(t-butyloxycarbonyl)-N-methylglycine (34 mg,0.18 mmol). Yield=25 mg (39%, two steps). LC/MS method A: R_(t)=3.99min., (M+H)⁺=391.05.

Example 112: Synthesis of2-(2-(ethylamino)acetamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

2-(2-(ethylamino)acetamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide was prepared according to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide(53 mg, 0.15 mmol) and N-(t-butyloxycarbonyl)-N-ethylglycine (37 mg,0.18 mmol). Yield=29 mg (44%, two steps). LC/MS method A: R_(t)=4.07min., (M+H)⁺=405.12.

Example 113: Synthesis of2-(2-(isopropylamino)acetamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

2-(2-(isopropylamino)acetamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamidewas prepared according to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide (53 mg, 0.15 mmol) andN-t-butyloxycarbonyl-N-isopropylglycine (39 mg, 0.18 mmol). Yield=29 mg(42%, two steps). LC/MS method A: R_(t)=4.17 min., (M+H)⁺=419.12.

Example 114: Synthesis of2-(2-(tert-butylamino)acetamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

2-(2-(tert-butylamino)acetamido)-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamidewas prepared according to the procedure of example 49 from2-amino-2-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide (53 mg, 0.15 mmol) andN-t-butyloxycarbonyl-N-t-butyl glycine (39 mg, 0.18 mmol). Yield=18 mg(22%, two steps). LC/MS method A: R_(t)=4.26 min., (M+H)⁺=433.13

Example 115: Synthesis of(S)-2-(2-aminoacetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

(S)-2-(2-aminoacetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamidewas prepared according to the procedure of example 49 from(S)-2-amino-N-(6-(trifluoromethoxy) benzo[d]thiazol-2-yl)propanamide (50mg, 0.146 mmol) and N-t-butyloxycarbonylglycine (33 mg, 0.19 mmol).Yield=35 mg (50%, two steps). LC/MS method A: R_(t)=3.73 min.,(M+H)⁺=362.98.

Example 116: Synthesis of(S)-2-amino-N—((S)-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamide

(S)-2-amino-N—((S)-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamidewas prepared according to the procedure of example 49 from(S)-2-amino-N-(6-(trifluoromethoxy) benzo[d]thiazol-2-yl)propanamide (50mg, 0.146 mmol) and N-t-butyloxycarbonylalanine (41 mg, 0.22 mmol).Yield=38 mg (53%, two steps). LC/MS method A: R_(t)=3.76 min.,(M+Na)⁺=398.93.

Example 117: Synthesis of(R)-2-amino-N—((S)-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamide

(R)-2-amino-N—((S)-1-oxo-1-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-yl)propanamidewas prepared according to the procedure of example 49 from(S)-2-amino-N-(6-(trifluoromethoxy) benzo[d]thiazol-2-yl)propanamide (50mg, 0.146 mmol) and N-t-butyloxycarbonyl-D-alanine (41 mg, 0.22 mmol).Yield=23 mg (32%, two steps). LC/MS method A: R_(t)=3.76 min.,(M+H)⁺=376.98.

Example 118: Synthesis of3-Amino-N,2,2-trimethyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

A solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidehydrochloride (25 mg, 73 μmol),3-((tert-butoxycarbonyl)amino)-2,2-dimethylpropanoic acid (19 mg, 88μmol) and N,N-diisopropylethylamine (24 mg, 180 μmol, 33 μl) inN,N-dimethylformamide (0.5 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (33 mg, 88 μmol) and stirred for 18 hours.The product was purified by reversed phase HPLC (method B, directinjection). The product was evaporated on a Genevac evaporator to leave36 mg (81%). The purified product was dissolved in 4N HCl/1,4-dioxane(0.5 ml) and stirred for 2 hours. The HCl/1,4-dioxane was evaporated toleave the product as a white solid, mono HCl salt. Yield=33 mg (100%,81% for two steps). LC/MS method A: R_(t)=3.88 min., (M+H)⁺=405.

Examples 119-125 were prepared under identical scale and method asexample 118 above:

Example 119: Synthesis of1-(aminomethyl)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclopropane-1-carboxamide

1-(aminomethyl)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclopropane-1-carboxamide was prepared according to theprocedure of example 118 from1-(((tert-butoxycarbonyl)amino)methyl)cyclopropane-1-carboxylic acid (19mg, 88 μmol). Yield=31 mg (98%, 80% for two steps). LC/MS method A:R_(t)=3.81 min., (M+H)⁺=403.

Example 120: Synthesis of1-(aminomethyl)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclopentane-1-carboxamide

1-(aminomethyl)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclopentane-1-carboxamide was prepared according to theprocedure of example 118 from1-(((tert-butoxycarbonyl)amino)methyl)cyclopentane-1-carboxylic acid (21mg, 88 μmol). Yield=33 mg (100%, 77% for two steps). LC/MS method A:R_(t)=4.07 min., (M+H)⁺=431.

Example 121: Synthesis of1-(aminomethyl)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexane-1-carboxamide

1-(aminomethyl)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexane-1-carboxamide was prepared according to theprocedure of example 118 from1-(((tert-butoxycarbonyl)amino)methyl)cyclohexane-1-carboxylic acid (23mg, 88 μmol). Yield=23 mg (100%, 48% for two steps). LC/MS method A:R_(t)=4.21 min., (M+H)⁺=445.

Example 122: Synthesis ofN-methyl-2-(methylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

N-methyl-2-(methylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide was prepared according to the procedure of example118 from N-(tert-butoxycarbonyl)-N-methylglycine (17 mg, 88 μmol).Yield=30 mg (100%, 86% for two steps). LC/MS method A: R_(t)=3.70 min.,(M+H)⁺=377.

Example 123: Synthesis of2-(ethylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

2-(ethylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide was prepared according to the procedure of example 118from N-(tert-butoxycarbonyl)-N-ethylglycine (18 mg, 88 μmol). Yield=32mg (100%, 86% for two steps).

LC/MS method A: R_(t)=3.78 min., (M+H)⁺=391.

Example 124: Synthesis of2-(isopropylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

2-(isopropylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamidewas prepared according to the procedure of example 118 fromN-(tert-butoxycarbonyl)-N-isopropylglycine (19 mg, 88 μmol). Yield=34 mg(100%, 81% for two steps). LC/MS method A: R_(t)=3.88 min., (M+H)⁺=405.

Example 125: Synthesis of2-(tert-butylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

2-(tert-butylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamidewas prepared according to the procedure of example 118 fromN-(tert-butoxycarbonyl)-N-tert-butylglycine (20 mg, 88 μmol). Yield=29mg (100%, 68% for two steps). LC/MS method A: R_(t)=3.99 min.,(M+H)⁺=419.

Example 126: Synthesis of2-(dimethylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

2-(dimethylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide was prepared according to the procedure of example49 from2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidehydrochloride (50 mg, 0.16 mmol) and N,N-dimethylglycine hydrochloride(25 mg, 0.18 mmol). Purified by reverse phase HPLC to leave the productas a mono TFA salt. Yield=64 mg (79%). LC/MS method B: R_(t)=1.41 min.,(M+H)⁺=391.

Example 127: Synthesis of2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide was prepared according to the procedure of example 49 from2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidehydrochloride (50 mg, 0.16 mmol) and N-(tert-butoxycarbonyl)glycine (36mg, 0.21 mmol). Yield=38 mg (65%, two steps). LC/MS method A: R_(t)=3.64min., (M+H)⁺=362.98.

Example 128: Synthesis of(S)-2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

(S)-2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide was prepared according to the procedure of example 49from2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidehydrochloride (50 mg, 0.16 mmol) and N-(tert-butoxycarbonyl)alanine (41mg, 0.22 mmol). Yield=45 mg (75%, two steps). LC/MS method A: R_(t)=3.76min., (M+Na)⁺=398.93.

Example 129: Synthesis of(R)-2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

(R)-2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide was prepared according to the procedure of example 49from2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidehydrochloride (50 mg, 0.16 mmol) and N-(tert-butoxycarbonyl)-D-alanine(41 mg, 0.22 mmol). Yield=45 mg (75%, two steps). LC/MS method A:R_(t)=3.76 min., (M+Na)⁺=398.93.

Example 130: Synthesis of3-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide

3-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)propanamide was prepared according to the procedure of example 49 from2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidehydrochloride (34 mg, 0.10 mmol) andN-(tert-butoxycarbonyl)-beta-alanine (33 mg, 0.17 mmol). Yield=35 mg(58%, two steps). LC/MS method A: R_(t)=3.69 min., (M+H)⁺=376.91.

Example 131: Synthesis of2-amino-N-ethyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

2-amino-N-ethyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide was prepared according to the procedure of example 49 from2-(ethylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidehydrochloride (35 mg, 0.10 mmol) and N-(tert-butoxycarbonyl)glycine (23mg, 0.13 mmol). Yield=32 mg (77%, two steps). LC/MS method A: R_(t)=3.76min., (M+H)⁺=376.98.

Example 132: Synthesis of2-amino-N-isopropyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

2-amino-N-isopropyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide was prepared according to the procedure of example 49from 2-(isopropylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidehydrochloride (37 mg, 0.10 mmol) and N-(tert-butoxycarbonyl)glycine (23mg, 0.13 mmol). Yield=32 mg (75%, two steps). LC/MS method A: R_(t)=3.88min., (M+H)⁺=390.91.

Example 133: Synthesis of2-(aminomethyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)benzamide

A solution of 2-amino-6-(trifluoromethoxy)benzo[d]thiazole (100 mg, 0.43mmol), 2-N-((tert-butoxy carbonyl)aminomethyl)benzoic acid (161 mg, 0.64mmol) and N, N-diisopropyl ethylamine (83 mg, 0.64 mmol, 115 μl) inN,N-dimethylformamide (2 ml) was treated with 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate(243 mg, 0.64 mmol) and stirred for 72 hours. The reaction mixture wasdiluted with ethyl acetate (50 ml), washed with water (2×25 ml) and 1NHCl (25 ml). The solvents were evaporated and the residue waschromatographed on silica gel eluted with a gradient of 10% ethylacetate in hexanes to 50% ethyl acetate in hexanes. The product (87 mg,43%) was dissolved in 4N HCl/1,4-dioxane, stirred for 2 hours thenevaporated to dryness. The white powdery mono hydrochloride productweighed 77 mg (100%, 43% for two steps). LC/MS method A: R_(t)=3.97min., (M+H)⁺=368.

Example 134: Synthesis of tert-butyl(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)carbamate

A solution of 2-amino-6-(trifluoromethoxy)benzo[d]thiazole (2.0 g, 8.5mmol), N-(tert-butyloxycarbonyl)-4-aminobutyric acid (2.6 g, 12.8 mmol)and N,N-diisopropylethylamine (1.7 g, 12.8 mmol, 2.3 ml) inN,N-dimethylformamide (40 ml) was treated with 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate(4.9 g, 12.8 mmol) and stirred for 18 h. Ethyl acetate (200 ml) wasadded to the reaction mixture and it was washed with water (2×150 ml),1N HCl (2×100 ml), saturated aqueous sodium bicarbonate (100 ml) andbrine (100 ml). The organic layer was dried (Na₂SO₄) and evaporated toleave a light yellow crystalline solid (2.9 g, 81%). LC/MS method A:R_(t)=5.88 min., (M+H)⁺=420.42.

Synthesis of4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide

A solution of tert-butyl(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)carbamate (2.8 g, 6.7 mmol) in 1,4-dioxane (35 ml) and 4NHCl/1,4-dioxane (35 ml) was stirred for 18 h. The white precipitate wasfiltered on a medium glass frit and washed with 1,4-dioxane and ether.The solid was dried under vacuum to leave 2.55 g (97%). LC/MS method A:R_(t)=3.68 min., (M+H)⁺=320.30.

Synthesis of(S)—N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)pyrrolidine-2-carboxamide

A solution of4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (25 mg,65 μmol and N,N-diisopropylethylamine (17 mg, 0.13 mmol, 23 μl) inN,N-dimethylformamide (0.5 ml) was treated with 1-(tert-butyl)2-(2,5-dioxopyrrolidin-1-yl) (S)-pyrrolidine-1,2-dicarboxylate (22 mg,70 μmol) and stirred 18 h. The product was purified by direct injectionreverse phase HPLC (method B) and the product fractions were evaporatedon a Genevac evaporator to leave the product as a gum (29 mg) which wasdissolved in 1,4-dioxane (1 ml) and 4N HCl/1,4-dioxane (1 ml). Afterstirring for 4 h the solvents were evaporated to leave the product as awhite solid (26 mg, 83%). LC/MS method A: R_(t)=3.85 min., (M+H)⁺=417.

Example 135: Synthesis of(S)-2-amino-4-methyl-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)pentanamide

A solution of4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (25 mg,65 μmol and N,N-diisopropylethylamine (17 mg, 0.13 mmol, 23 μl) inN,N-dimethylformamide (0.5 ml) was treated with 2,5-dioxopyrrolidin-1-yl(tert-butoxycarbonyl)-L-leucinate (23 mg, 70 μmol) and stirred 18 h. Theproduct was purified by direct injection reverse phase HPLC (method B)and the product fractions were evaporated on a Genevac evaporator toleave the product as a gum (29 mg) which was dissolved in 1,4-dioxane (1ml) and 4N HCl/1,4-dioxane (1 ml). After stirring for 4 h the solventswere evaporated to leave the product as a white solid (28 mg, 87%).LC/MS method A: R_(t)=4.14 min., (M+H)⁺=433.

Example 136: Synthesis of4-(2-aminoacetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide

A solution of4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (25 mg,65 μmol), N-(tert-butoxycarbonyl)-L-glycine (13 mg, 76 μmol) andN,N-diisopropylethylamine (18 mg, 0.14 mmol, 25 μl) inN,N-dimethylformamide (0.5 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (27 mg, 70 μmol) and stirred 18 hours. Theproduct was purified by direct injection reverse phase HPLC (method B)and the product fractions were evaporated on a Genevac evaporator toleave the product as a gum (17 mg, 54%) which was dissolved in1,4-dioxane (1 ml) and 4N HCl/1,4-dioxane (1 ml). After stirring for 4hours the solvents were evaporated to leave the product as a white solid(12 mg, 46% for two steps). LC/MS method A: R_(t)=3.71 min., (M+H)⁺=377.

Examples 137-146 were prepared in identical scale and method to example136 above.

Example 137: Synthesis of(S)-4-(2-aminopropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide

(S)-4-(2-aminopropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamidewas prepared according to the procedure of example 136 from4-amino-N-(6-(trifluoromethoxy) benzo[d]thiazol-2-yl)butanamide (25 mg,65 μmol) and N-(tert-butoxycarbonyl)-L-alanine to leave 16 mg (59% fortwo steps). LC/MS method A: R_(t)=3.75 min., (M+H)⁺=391.

Example 138: Synthesis of(S)-2-amino-3-methyl-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)butanamide

(S)-2-amino-3-methyl-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)butanamide was prepared according to the procedure of example 136from 4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (25mg, 65 μmol) and N-(tert-butoxy carbonyl)-L-Valine to leave 16 mg (59%for two steps). LC/MS method A: R_(t)=3.95 min., (M+H)⁺=419.

Example 139: Synthesis of(S)-5-oxo-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)pyrrolidine-2-carboxamide

(S)-5-oxo-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 136 from4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (25 mg,65 μmol) and L-pyroglutamate to leave 14 mg (47% for two steps). LC/MSmethod A: R_(t)=4.22 min., (M+H)⁺=431.

Example 140: Synthesis of(2S,3S)-2-amino-3-methyl-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)pentanamide

(2S,3S)-2-amino-3-methyl-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)pentanamide was prepared according to the procedure of example 136from 4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (25mg, 65 μmol) and N-(tert-butoxy carbonyl)-L-isoleucine to leave 14 mg(47% for two steps). LC/MS method A: R_(t)=4.11 min., (M+H)⁺=433.

Example 141: Synthesis of(S)-4-amino-5-oxo-5-((4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)amino)pentanoic acid

(S)-4-amino-5-oxo-5-((4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)amino)pentanoic acid was prepared according to the procedure of example136 from 4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide(25 mg, 65 μmol) and N-(tert-butoxycarbonyl)-L-glutamine to leave 16 mg(52% for two steps). LC/MS method A: R_(t)=3.62 min., (M+H)⁺=448.

Example 142: Synthesis of(S)-2-amino-4-(methylthio)-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)butanamide

(S)-2-amino-4-(methylthio)-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)butanamide was prepared according to the procedure ofexample 136 from4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (25 mg,65 μmol) and N-(tert-butoxycarbonyl)-L-methionine to leave 16 mg (51%for two steps). LC/MS method A: R_(t)=4.02 min., (M+H)⁺=451.

Example 143:(S)-4-(2-amino-3-phenylpropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide

(S)-4-(2-amino-3-phenylpropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamidewas prepared according to the procedure of example 136 from4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (25 mg,65 μmol) and N-(tert-butoxycarbonyl)-L-phenylalanine to leave 16 mg (50%for two steps). LC/MS method A: R_(t)=4.20 min., (M+H)⁺=467.

Example 144: Synthesis of(S)-3-amino-4-oxo-4-((4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)amino)butanoic acid

(S)-3-amino-4-oxo-4-((4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)amino)butanoic acid was prepared according to the procedure of example136 from 4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide(25 mg, 65 μmol) and N-(tert-butoxycarbonyl)-aspartic acid betatert-butyl ester to leave 18 mg (60% for two steps). LC/MS method A:R_(t)=3.72 min., (M+H)⁺=435.

Example 145: Synthesis of(S)-4-amino-5-oxo-5-((4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)amino)pentanoic acid

(S)-4-amino-5-oxo-5-((4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)amino)pentanoic acid was prepared according to the procedure of example136 from 4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide(25 mg, 65 μmol) and N-(tert-butoxy carbonyl)-L-glutamine gammatert-butyl ester to leave 16 mg (52% for two steps). LC/MS method A:R_(t)=3.72 min., (M+H)⁺=449.

Example 146: Synthesis of(S)-4-(2-amino-3-(1H-indol-3-yl)propanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide

(S)-4-(2-amino-3-(1H-indol-3-yl)propanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide was prepared according to the procedure ofexample 136 from4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (25 mg,65 μmol) and N-(tert-butoxy carbonyl)-L-tryptophan to leave 20 mg (71%for two steps). LC/MS method A: R_(t)=4.24 min., (M+H)⁺=506.

Example 147: Synthesis of(S)—N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)pyrrolidine-2-carboxamideSynthesis of tert-butyl ((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)carbamate

A solution of 2-amino-6-(trifluoromethoxy)benzo[d]thiazole (0.50 g, 2.1mmol), 2-(1-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl)acetic acid(0.74 g, 2.7 mmol) and N,N-diisopropylethylamine (0.35 g, 2.7 mmol,2.30.48 ml) in N,N-dimethylformamide (10 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (1.0 g, 2.7 mmol) and stirred for 18 hours.Ethyl acetate (100 ml) was added to the reaction mixture and it waswashed with water (2×50 ml), 1N HCl (100 ml), saturated aqueous sodiumbicarbonate (100 ml) and brine (50 ml). The organic layer was dried(Na₂SO₄) and evaporated. The crude product was chromatographed on silicagel with a gradient of 20% to 25% ethyl acetate in hexanes to leave theproduct as a white crystalline solid (0.44 g, 43%). LC/MS method A:R_(t)=7.36 min., (M+H)⁺=488.

Synthesis of2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide

A solution of tert-butyl((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)carbamate (0.42 g, 0.86 mmol) in 1,4-dioxane (10ml) and 4N HCl/1,4-dioxane (10 ml) was stirred for 18 hours. Thesolvents were evaporated to leave the product as a white solid (0.38 g,100%). LC/MS method A: R_(t)=4.27 min., purity >95%, (M+H)⁺=388.

Synthesis of(S)—N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)pyrrolidine-2-carboxamide

A solution of2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol) and N,N-diisopropylethylamine (15 mg, 0.12 mmol, 21 μl)in N,N-dimethylformamide (0.5 ml) was treated with 1-(tert-butyl)2-(2,5-dioxopyrrolidin-1-yl) (S)-pyrrolidine-1,2-dicarboxylate (18 mg,56 μmol) and stirred 18 h. The product was purified by direct injectionreverse phase HPLC (method B) and the product fractions were evaporatedon a Genevac evaporator to leave the product which was dissolved in1,4-dioxane (1 ml) and 4N HCl/1,4-dioxane (1 ml). After stirring for 4 hthe solvents were evaporated to leave the product as a white solid (21mg, 92%). LC/MS method A: R_(t)=4.75 min., (M+H)⁺=485.

Examples 148-149 were prepared in identical scale and method to example147 above.

Example 148: Synthesis of(S)-2-amino-4-methyl-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)pentanamide

(S)-2-amino-4-methyl-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)pentanamidewas prepared according to the procedure of example 147 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol) and 2,5-dioxopyrrolidin-1-yl L-leucinate to leave 23 mg(94% for two steps). LC/MS method A: R_(t)=5.04 min., (M+H)⁺=501.

Example 149: Synthesis of(S)-2-amino-3-methyl-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)butanamide

(S)-2-amino-3-methyl-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)butanamide was prepared according to theprocedure of example 147 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol) and 2,5-dioxopyrrolidin-1-yl L-valinate to leave 15 mg(66% for two steps). LC/MS method A: R_(t)=4.87 min., (M+H)⁺=487.

Example 150: Synthesis of2-amino-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)acetamide

A solution of2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol), N-(tert-butoxycarbonyl)-L-glycine (10 mg, 57 μmol) andN,N-diisopropylethylamine (15 mg, 0.12 mmol, 22 μl) inN,N-dimethylformamide (0.5 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (22 mg, 57 μmol) and stirred 18 hours. Theproduct was purified by direct injection reverse phase HPLC (method B)and the product fractions were evaporated on a Genevac evaporator toleave the product as a gum (13 mg, 51%) which was dissolved in1,4-dioxane (1 ml) and 4N HCl/1,4-dioxane (1 ml). After stirring for 4hour the solvents were evaporated to leave the product as a white solid(10 mg, 47% for two steps). LC/MS method A: R_(t)=4.53 min., (M+H)⁺=445.

Examples 151-160 were prepared in identical scale and method to example150 above.

Example 151: Synthesis of(S)-2-amino-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)propanamide

(S)-2-amino-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)propanamide was prepared according to the procedure ofexample 150 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol and (tert-butoxycarbonyl)-L-alanine to leave 9 mg (39%for two steps). LC/MS method A: R_(t)=4.61 min., (M+H)⁺=459.

Example 152: Synthesis of2-(methylamino)-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)acetamide

2-(methylamino)-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)acetamide was prepared according to the procedure ofexample 150 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol) and (tert-butoxycarbonyl)-sarcosine to leave 15 mg (65%for two steps). LC/MS method A: R_(t)=4.60 min., (M+H)⁺=459.

Example 153: Synthesis of(R)-2-amino-3-methyl-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)butanamide

(R)-2-amino-3-methyl-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)butanamidewas prepared according to the procedure of example 150 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol) and (tert-butoxycarbonyl)-D-valine to leave 11 mg (45%for two steps). LC/MS method A: R_(t)=4.86 min., (M+H)⁺=487.

Example 154: Synthesis of(S)-5-oxo-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)pyrrolidine-2-carboxamide

(S)-5-oxo-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)pyrrolidine-2-carboxamide was prepared according tothe procedure of example 150 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol) and L-pyroglutamate to leave 12 mg (45% for two steps).LC/MS method A: R_(t)=4.41 min., (M+H)⁺=499.

Example 155: Synthesis of(S)-2-amino-N1-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)pentanediamide

(S)-2-amino-N1-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)pentanediamide was prepared according to the procedureof example 150 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol) and (tert-butoxycarbonyl)-L-glutamine to leave 5 mg(19% for two steps). LC/MS method A: R_(t)=4.42 min., (M+H)⁺=516.

Example 156: Synthesis of(S)-2-amino-4-(methylthio)-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)butanamide

(S)-2-amino-4-(methylthio)-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)butanamidewas prepared according to the procedure of example 150 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol) and (tert-butoxycarbonyl)-L-methionine to leave 12 mg(46% for two steps). LC/MS method A: R_(t)=4.90 min., (M+H)⁺=519.

Example 157: Synthesis of(S)-2-amino-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzothiazol-2-yl)amino)ethyl)cyclohexyl)methyl)-3-phenylpropanamide

(S)-2-amino-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)-3-phenylpropanamide was prepared according to theprocedure of example 150 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol) and (tert-butoxycarbonyl)-L-phenylalanine to leave 13mg (49% for two steps). LC/MS method A: R_(t)=5.10 min., (M+H)⁺=535.

Example 158: Synthesis of(S)-3-amino-4-oxo-4-(((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)amino)butanoic acid

(S)-3-amino-4-oxo-4-(((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)amino)butanoic acid was prepared according tothe procedure of example 150 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol) and N-(tert-butoxycarbonyl)-L-aspartyl-beta-tert-butylester to leave 13 mg (51% for two steps). LC/MS method A: R_(t)=4.51min., (M+H)⁺=503.

Example 159: Synthesis of(S)-4-amino-5-oxo-5-(((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)amino)pentanoic acid

(S)-4-amino-5-oxo-5-(((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)amino)pentanoic acid was prepared according tothe procedure of example 150 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol) and N-(tert-butoxycarbonyl)-L-glutamyl-gamma-tert-butylester to leave 14 mg (54% for two steps). LC/MS method A: R_(t)=4.52min., (M+H)⁺=517.

Example 160: Synthesis of(S)-2-amino-3-(1H-indol-3-yl)-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)propanamide

(S)-2-amino-3-(1H-indol-3-yl)-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)propanamidewas prepared according to the procedure of example 150 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(20 mg, 47 μmol) and N-(tert-butoxycarbonyl)-L-tryptophan to leave 11 mg(38% for two steps). LC/MS method A: R_(t)=5.06 min., (M+H)⁺=574.

Example 161: Synthesis of(R)-2-amino-3-methyl-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)butanamide

A solution of4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (20 mg,56 μmol), N-(tert-butoxycarbonyl)-D-valine (16 mg, 73 μmol) andN,N-diisopropylethylamine (22 mg, 0.17 mmol, 30 μl) inN,N-dimethylformamide (0.5 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (28 mg, 73 μmol) and stirred 18 hours. Theproduct was purified by direct injection reverse phase HPLC (method B)and the product fractions were evaporated on a Genevac evaporator toleave the product as a gum (21 mg, 72%) which was dissolved in1,4-dioxane (1 ml) and 4N HCl/1,4-dioxane (1 ml). After stirring for 4hours the solvents were evaporated to leave the product as a white solid(19 mg, 72% for two steps). LC/MS method A: R_(t)=4.01 min., (M+H)⁺=419.

Examples 162-163 were prepared in identical scale and method to example161 above.

Example 162: Synthesis of(R)—N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)pyrrolidine-2-carboxamide

(R)—N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 161 from4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (20 mg,56 μmol) and N-(tert-butoxy carbonyl)-D-proline to leave 25 mg (76% fortwo steps). LC/MS method A: R_(t)=3.91 min., (M+H)⁺=417.

Example 163: Synthesis of(R)-5-oxo-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)pyrrolidine-2-carboxamide

(R)-5-oxo-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)pyrrolidine-2-carboxamidewas prepared according to the procedure of example 161 from4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide (20 mg,56 μmol) and D-pyroglutamate to leave 9 mg (37% for two steps). LC/MSmethod A: R_(t)=4.28 min., (M+H)⁺=431.

Example 164: Synthesis of(R)-2-amino-3-methyl-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)butanamide

A solution of2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(25 mg, 56 μmol), N-(tert-butoxycarbonyl)-D-valine (16 mg, 73 μmol) andN,N-diisopropylethylamine (22 mg, 0.17 mmol, 30 μl) inN,N-dimethylformamide (0.5 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidhexafluoro phosphate (28 mg, 73 μmol) and stirred 18 hours. The productwas purified by direct injection reverse phase HPLC (method B) and theproduct fractions were evaporated on a Genevac evaporator to leave theproduct as a gum (10 mg, 30%) which was dissolved in 1,4-dioxane (1 ml)and 4N HCl/1,4-dioxane (1 ml). After stirring for 4 hours the solventswere evaporated to leave the product as a white solid (8 mg, 27% for twosteps). LC/MS method A: R_(t)=4.86 min., (M+H)⁺=487.

Examples 165-166 were prepared in identical scale and method to example164 above.

Example 165: Synthesis of(S)—N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)pyrrolidine-2-carboxamide

(S)—N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)pyrrolidine-2-carboxamide was prepared according to the procedureof example 164 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(25 mg, 56 μmol) and (tert-butoxycarbonyl)-D-proline to leave 10 mg (34%for two steps). LC/MS method A: R_(t)=3.91 min., (M+H)⁺=417.

Example 166: Synthesis of(R)-5-oxo-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)pyrrolidine-2-carboxamide

(R)-5-oxo-N-((1-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)cyclohexyl)methyl)pyrrolidine-2-carboxamide: was prepared according tothe procedure of example 164 from2-(1-(aminomethyl)cyclohexyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(25 mg, 56 μmol) and D-pyroglutamate to leave 12 mg (43% for two steps).LC/MS method A: R_(t)=5.52 min., (M+H)⁺=499.

Example 167: Synthesis of4-amino-3,3-dimethyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide

A solution of 6-(trifluoromethoxy)benzo[d]thiazol-2-amine (37 mg, 0.16mmol), 4-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (55 mg,0.24 mmol), 1-hydroxy-7-azabenzotriazole (33 mg, 0.24 mmol) andN,N-diisopropylethylamine (31 mg, 0.24 mmol, 43 μl) inN,N-dimethylformamide (0.5 ml) was treated with1-methyl-2-chloropyridinium iodide (61 mg, 0.24 mmol) and stirred 4days. The product was purified by direct injection reverse phase HPLC(method B) and the product fractions were evaporated on a Genevacevaporator to leave the product as a solid (38 mg, 53%) which wasdissolved in 4N HCl/1,4-dioxane (1 ml). After stirring for 4 hours thesolvents were evaporated to leave the product as a white solid (34 mg,100%, 53% for two steps). LC/MS method A: R_(t)=3.95 min., (M+H)⁺=348.

Example 168: Synthesis of(S)-3-(benzyloxy)-2-morpholino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamideSynthesis of (R)-3-(benzyloxy)-2-bromopropanoic acid

A solution of O-benzyl-D-serine (1.0 g, 5.1 mmol) and potassium bromide(3.6 g, 30.6 mmol) in 2.5 N sulfuric acid (35 ml) in an ice bath wasstirred and treated with sodium nitrite (0.95 g, 14 mmol) in portionsover 30 mins. The mixture stirred an additional 60 mins., then ether (50ml) was added and the mixture stirred 30 mins. The organic layer wasseparated, washed with brine (25 ml), dried (Na₂SO₄) and evaporated toleave the product as a colorless oil (1.3 g, 98%).

Synthesis of Methyl (R)-3-(benzyloxy)-2-bromopropanoate

A solution of (R)-3-(benzyloxy)-2-bromopropanoic acid (1.2 g, 4.6 mmol)in anhydrous tetrahydrofuran (30 ml) and methanol (5 ml) in an ice bathwas treated with an ethereal solution of trimethylsilyldiazomethane (3.5ml, 7.0 mmol) and stirred for 30 minutes. Acetic acid (1 ml) was addedto the reaction mixture stirred an additional 30 mins. Approximatelyhalf of the solvent was evaporated in vacuo, ethyl acetate (50 ml) wasadded and the solution was washed with saturated sodium bicarbonatesolution (25 ml) and brine (25 ml). The organic phase was dried (MgSO₄)and evaporated. The crude product was purified by silica gelchromatography eluted with 10% ethyl acetate in hexanes to leave aclear, colorless oil (0.90 g, 72%). LC/MS method A: R_(t)=5.57 min.

Synthesis of Methyl (R)-3-(benzyloxy)-2-morpholinopropanoate

A solution of Methyl (R)-3-(benzyloxy)-2-bromopropanoate (100 mg, 0.36mmol) and morpholine (0.16 g, 1.8 mmol, 0.16 ml) inN,N-dimethylformamide (2 ml) was stirred for 5 days. The reactionmixture was diluted with ethyl acetate (25 ml) and washed with water (25ml), saturated sodium bicarbonate solution (25 ml) and brine (25 ml).The organic phase was dried (MgSO₄) and evaporated to leave the productas an oil (0.10 g, 100%). LC/MS method A: R_(t)=2.95 min., (M+H)⁺=280.

Synthesis of (S)-3-(benzyloxy)-2-morpholinopropanoic acid

A solution of Methyl (R)-3-(benzyloxy)-2-morpholinopropanoate (95 mg,0.34 mmol) and lithium hydroxide monohydrate (57 mg, 1.4 mmol) intetrahydrofuran (2 ml) and water (3 ml) was stirred for 1.5 hours. Thereaction mixture was purified by reverse phase HPLC (method B) and theproduct fractions were evaporated on a Genevac evaporator to leave thepure product as a TFA salt (62 mg, 48%). LC/MS method A: R_(t)=2.5 min.,(M+H)⁺=266.

Synthesis of(S)-3-(benzyloxy)-2-morpholino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

A solution of (S)-3-(benzyloxy)-2-morpholinopropanoic acid TFA salt (55mg, 0.15 mmol), 6-(trifluoromethoxy)benzo[d]thiazol-2-amine (68 mg, 0.30mmol), 1-hydroxy-7-azabenzotriazole (23 mg, 0.17 mmol) andN,N-diisopropylethylamine (58 mg, 0.45 mmol, 81 μl) inN,N-dimethylformamide (0.5 ml) was treated with1-methyl-2-chloropyridinium iodide (43 mg, 0.17 mmol) and the mixturewas stirred for 18 hours. The reaction mixture was purified by reversephase HPLC. The acetonitrile was evaporated from the product fractionsand the aqueous residue was diluted with saturated sodium bicarbonatesolution (25 ml) and ethyl acetate (50 ml). The organic phase wasseparated, washed with brine (25 ml), dried (MgSO₄) and evaporated. Theresidue was dissolved in 1,4-dioxane (2 ml) and treated with 4N HCl in1,4-dioxane (1 ml). The mixture was evaporated to leave the monohydrochloride salt of the product (60 mg, 77%). LC/MS method A:R_(t)=4.82 min., (M+H)⁺=482.

Example 169: Synthesis of(S)-3-(benzyloxy)-2-(dimethylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide Synthesis of MethylO-benzyl-N,N-dimethyl-L-serinate

A solution of methyl (R)-3-(benzyloxy)-2-bromopropanoate (100 mg, 0.36mmol) and dimethylamine (5.6 M in ethanol, 1.9 mmol, 0.34 ml) inN,N-dimethylformamide (2 ml) was stirred for 18 hours. The reactionmixture was diluted with ethyl acetate (25 ml) and washed with water (25ml) and brine (25 ml). The organic phase was dried (MgSO₄) andevaporated to leave the product as an oil (83 mg, 95%). LC/MS method A:R_(t)=2.94 min., (M+H)⁺=238.

Synthesis of O-benzyl-N,N-dimethyl-L-serine

A solution of methyl O-benzyl-N,N-dimethyl-L-serinate (75 mg, 0.32 mmol)and lithium hydroxide monohydrate (53 mg, 1.3 mmol) in tetrahydrofuran(2 ml) and water (3 ml) was stirred for 1 hour. The reaction mixture waspurified by reverse phase HPLC (method B) and the product fractions wereevaporated on a Genevac evaporator to leave the pure product as a TFAsalt (110 mg, 100%). LC/MS method A: R_(t)=2.53 min.

Synthesis of(S)-3-(benzyloxy)-2-(dimethylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

A solution of O-benzyl-N,N-dimethyl-L-serine TFA salt (52 mg, 0.22mmol), 6-(trifluoromethoxy)benzo[d]thiazol-2-amine (50 mg, 0.15 mmol),1-hydroxy-7-azabenzotriazole (29 mg, 0.22 mmol) andN,N-diisopropylethylamine (58 mg, 0.45 mmol, 81 μl) inN,N-dimethylformamide (0.5 ml) was treated with1-methyl-2-chloropyridinium iodide (56 mg, 0.22 mmol) and the mixturewas stirred for 18 hours. The reaction mixture was purified by reversephase HPLC. The acetonitrile was evaporated from the product fractionsand the aqueous residue was diluted with saturated sodium bicarbonatesolution (25 ml) and ethyl acetate (50 ml). The organic phase wasseparated, washed with brine (25 ml), dried (MgSO₄) and evaporated. Theresidue was dissolved in 1,4-dioxane (2 ml) and treated with 4N HCl in1,4-dioxane (1 ml). The mixture was evaporated to leave the monohydrochloride salt of the product (21 mg, 29%). LC/MS method A:R_(t)=2.70 min., (M+H)⁺=440.

Example 170: Synthesis of(S)-1-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

A solution of N-methyl-L-proline (55 mg, 0.42 mmol),6-(trifluoromethoxy)benzo[d] thiazol-2-amine (50 mg, 0.21 mmol),1-hydroxy-7-azabenzotriazole (56 mg, 0.42 mmol) andN,N-diisopropylethylamine (54 mg, 0.42 mmol, 75 μl) inN,N-dimethylformamide (0.5 ml) was treated with1-methyl-2-chloropyridinium iodide (107 mg, 0.42 mmol) and the mixturewas stirred for 18 hours. The reaction mixture was purified by reversephase HPLC. The product fractions were combined, treated with saturatedsodium bicarbonate (25 ml) and extracted with ethyl acetate (2×25 ml).The combined extracts were washed with brine (25 ml), dried (MgSO₄) andevaporated. The residue was dissolved in 1,4-dioxane (2 ml) and treatedwith 4N HCl in 1,4-dioxane (1 ml). The mixture was evaporated to leavethe mono hydrochloride salt of the product (67 mg, 84%). LC/MS method A:R_(t)=3.77 min., (M+H)⁺=346.

Example 171: Synthesis of2-(ethylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

A solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(50 mg, 0.16 mmol), N-(tert-butoxycarbonyl)-N-ethylglycine (37 mg, 0.18mmol) and N,N-diisopropylethylamine (46 mg, 0.36 mmol, 65 μl) inN,N-dimethylformamide (1 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (68 mg, 0.18 mmol) and stirred 18 hours. Theproduct was purified by direct injection reverse phase HPLC (method B)and the product fractions were evaporated on a Genevac evaporator toleave the product as a gum (56 mg, 71%) which was dissolved in 4NHCl/1,4-dioxane (2 ml). After stirring for 2 hours the solvents wereevaporated to leave the product as a white solid (43 mg, 63% for twosteps). LC/MS method C: R_(t)=1.41 min., (M+H)⁺=391.

Example 172 was prepared under identical scale and conditions as example171 above.

Example 172: Synthesis of2-(isopropylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

2-(isopropylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide:was prepared according to the procedure of example 171 from2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(50 mg, 0.16 mmol) and N-(tert-butoxycarbonyl)-N-isopropylglycine toleave 43 mg (63% for two steps). LC/MS method C: R_(t)=1.44 min.,(M+H)⁺=405.

Example 173: Synthesis of(R)-1-(1-(aminomethyl)cyclohexane-1-carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide

A solution of(R)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(200 mg, 0.54 mmol),1-(((tert-butoxycarbonyl)amino)methyl)cyclohexane-1-carboxylic acid (168mg, 0.65 mmol) and N,N-diisopropylethylamine (168 mg, 1.3 mmol, 233 μl)in N,N-dimethylformamide (3 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (247 mg, 0.65 mmol) and stirred 18 hours. Thereaction mixture was diluted with ethyl acetate (50 ml) and washed withwater (50 ml), 1N HCl (50 ml), water (50 ml), saturated sodiumbicarbonate solution (50 ml) and brine (25 ml). The organic layer wasdried (MgSO₄) and evaporated. The product was purified by chromatographyon silica gel eluted with a gradient of ethyl acetate in hexanes(10-40%) to leave the pure product as a foamy solid (220 mg, 71%). Thisproduct was dissolved in 4N HCl/1,4-dioxane (2 ml). After stirring for 2hours the solvents were evaporated to leave the product as a white solid(188 mg, 69% for two steps). LC/MS method A: R_(t)=4.40 min.,(M+H)⁺=471.

Example 174: Synthesis ofN-methyl-2-(methylsulfonamido)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

A solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide(25 mg, 73 μmol), (methylsulfonyl)glycine (12 mg, 88 μmol) andN,N-diisopropylethylamine (24 mg, 183 μmol, 33 μl) inN,N-dimethylformamide (0.5 ml) was treated with 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidhexafluorophosphate (33 mg, 88 μmol and stirred 18 hours. The reactionmixture was diluted with ethyl acetate (25 ml) and washed with water (25ml), 1N HCl (25 ml) and brine (25 ml). The organic layer was dried(MgSO₄) and evaporated. The product was purified by reverse phase HPLC(method B) to leave the pure product as a crystalline solid (11 mg,34%). LC/MS method C: R_(t)=2.06 min., (M+H)⁺=441.

Example 175: Synthesis of2-(tert-butoxy)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

A solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidemonohydrochloride (50 mg, 0.15 mmol), 2-(tert-butoxy)acetic acid (22 mg,0.17 mmol) and N,N-diisopropylethylamine (45 mg, 0.35 mmol, 63 μl) inN,N-dimethylformamide (1 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluoro phosphate (57 mg, 0.15 mmol) and stirred 3 hours. Theproduct was purified by reverse phase HPLC (method B) and the combinedproduct fractions were evaporated to leave the pure product as a stickysolid (59 mg, 93%). LC/MS method C: R_(t)=2.26 min., (M+H)⁺=420.

Example 176: Synthesis ofN,4,4-trimethyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pentanamide

N,4,4-trimethyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)pentanamide was prepared according to the procedure of example 175 from2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidemonohydrochloride (50 mg, 0.15 mmol) and 4,4-dimethylpentanoic acid onthe same scale as example 175 to leave 50 mg (80%) of product. LC/MSmethod C: R_(t)=2.50 min., (M+H)⁺=418.

Example 177: Synthesis of tert-Butyl(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)(1-(trifluoromethyl)cyclopropyl)carbamateSynthesis of Benzyl (1-(trifluoromethyl)cyclopropyl)carbamate

A solution of 1-(trifluoromethyl)cyclopropan-1-amine hydrochloride (0.15g, 0.93 mmol) and N,N-diisopropylethylamine (0.28 g, 2.2 mmol, 0.39 ml)in dichloromethane (5 ml) was cooled in an ice bath and treated withbenzyl chloroformate (0.17 g, 1.0 mmol, 0.143 ml). The mixture wasallowed to warm to 20° C. over 2 hours and stirred an additional 72hours. The mixture was diluted with ethyl acetate (50 ml), washed with1N HCl (25 ml) and brine (25 ml). The organic phase was dried (MgSO₄)and evaporated to leave the product as a solid (135 mg, 56%).

Synthesis of tert-butylN-((benzyloxy)carbonyl)-N-(1-(trifluoromethyl)cyclopropyl) glycinate

A solution of benzyl (1-(trifluoromethyl)cyclopropyl)carbamate (130 mg,0.50 mmol) in anhydrous tetrahydrofuran (4 ml) under nitrogen atmospherein an ice bath was treated with a solution of lithiumhexamethyldisilylamide (1.0 M in tetrahydrofuran, 0.60 ml, 0.60 mmol)dropwise over 5 minutes. The mixture stirred 30 minutes then 1-bromotert-butylacetate was added and stirring continued for an additional 18hours. The reaction mixture was treated with saturated aqueous ammoniumchloride (1 ml) and stirred 30 minutes. Ethyl acetate (50 ml) was addedand the mixture was washed with water (25 ml) and brine (25 ml). Theorganic phase was dried (MgSO₄) and evaporated. The crude product waspurified by silica gel chromatography eluting with a gradient of ethylacetate in hexanes (0-30%) to leave the product as a colorless oil (143mg, 77%). LC/MS method C: R_(t)=2.69 min.

Synthesis ofN-((Benzyloxy)carbonyl)-N-(1-(trifluoromethyl)cyclopropl)glycine

A solution of tert-butylN-((benzyloxy)carbonyl)-N-(1-(trifluoromethyl)cyclopropyl) glycinate(140 mg, 0.37 mmol) in TFA (1.5 ml) and dichloromethane (1.5 ml) wasstirred 2 hours then evaporated. Left 117 mg (100%). LC/MS method C:R_(t)=2.13 min.

Synthesis of tert-Butyl(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)(1-(trifluoromethyl)cyclopropyl)carbamate

A solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidemonohydrochloride (120 mg, 0.35 mmol),N-((benzyloxy)carbonyl)-N-(1-(trifluoromethyl) cyclopropyl)glycine (111mg, 0.35 mmol) and N,N-diisopropylethylamine (181 mg, 1.4 mmol, 251 μl)in N,N-dimethylformamide (3 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (133 mg, 0.35 mmol) and stirred 4 hours. Themixture was diluted with ethyl acetate (50 ml), washed with water (25ml), 1N HCl (25 ml) and brine (25 ml). The organic phase was dried(MgSO₄) and evaporated and the crude product was purified bychromatography on silica gel eluted with a gradient of ethyl acetate inhexanes (20%-100%) to leave the pure product as a gum (193 mg, 91%).LC/MS method C: R_(t)=2.60 min., (M+H)⁺=605.

Synthesis ofN-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)-2-((1-(trifluoromethyl)cyclopropyl)amino)acetamide

A solution of tert-Butyl(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)(1-(trifluoromethyl)cyclopropyl)carbamate(50 mg, 83 μmol in concentrated hydrobromic acid in acetic acid (2 ml)stirred for 18 hours and evaporated. The residue was dissolved in water(2 ml) and purified by reverse phase HPLC (method B). The productfractions were evaporated to leave the pure product as a TFA salt (25mg, 52%). LC/MS method C: R_(t)=2.40 min., (M+H)⁺=471.

Example 178: Synthesis ofN-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)-2-((2,2,2-trifluoroethyl)amino)acetamidehydrochloride Synthesis of tert-Butyl (2,2,2-trifluoroethyl)carbamate

A solution of 2,2,2-trifluoroethylamine hydrochloride (1.0 g, 7.4 mmol)in 1,4-dioxane (15 ml) and water (15 ml) was treated with sodiumcarbonate (0.78 g, 7.4 ml) and stirred 5 minutes.Di-tert-butyldicarbonate (1.4 g, 6.6 mmol) was added and the mixturestirred 20 hours. Dichloromethane (50 ml) was added to the reactionmixture and it was washed with saturated sodium bicarbonate solution (50ml). The aqueous layer was back-extracted with dichloromethane (50 ml)and the combined dichloromethane layers were washed with brine, dried(MgSO₄) and evaporated to leave a white solid (964 mg, 65%).

Synthesis of BenzylN-(tert-butoxycarbonyl)-N-(2,2,2-trifluoroethyl)glycinate

A solution of tert-Butyl (2,2,2-trifluoroethyl)carbamate (300 mg, 1.50mmol) in anhydrous tetrahydrofuran (15 ml) under nitrogen atmosphere inan ice bath was treated with a solution of lithiumhexamethyldisilylamide (1.0 M in tetrahydrofuran, 1.8 ml, 1.8 mmol)dropwise over 5 minutes. The mixture stirred 30 minutes then 1-bromobenzylacetate (518 mg, 2.25 mmol, 0.357 ml) was added and stirringcontinued for an additional 18 hours. The reaction mixture was treatedwith saturated aqueous ammonium chloride (3 ml) and stirred 30 mins.Ethyl acetate (50 ml) was added and the mixture was washed with water(25 ml) and brine (25 ml). The organic phase was dried (MgSO₄) andevaporated. The crude product was purified by silica gel chromatographyeluting with a gradient of ethyl acetate in hexanes (0-30%) to leave theproduct as a colorless oil (335 mg, 65%). LC/MS method C: R_(t)=2.62min.

Synthesis of N-(tert-Butoxycarbonyl)-N-(2,2,2-trifluoroethyl)glycine

Benzyl N-(tert-butoxycarbonyl)-N-(2,2,2-trifluoroethyl)glycinate (170mg, 0.49 mmol) was hydrogenated (45 psi initial pressure) over 10% Pd/C(30 mg) in methanol (4 ml). After 18 hours the catalyst was filteredthrough celite (methanol wash) and the filtrate was evaporated to leavethe product as a crystalline solid (126 mg, 100%).

Synthesis ofN-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)-2-((2,2,2-trifluoroethyl)amino)acetamidehydrochloride

A solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidemonohydrochloride (160 mg, 0.47 mmol),N-(tert-butoxycarbonyl)-N-(2,2,2-trifluoroethyl) glycine (120 mg, 0.47mmol) and N,N-diisopropylethylamine (152 mg, 1.2 mmol, 211 μl) inN,N-dimethylformamide (3 ml) was treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (179 mg, 0.47 mmol) and stirred 18 hours. Themixture was diluted with ethyl acetate (50 ml), washed with water (25ml), 1N HCl (25 ml) and brine (25 ml). The organic phase was dried(MgSO₄) and evaporated and the crude product was purified by reversephase HPLC. The product fractions were combined, treated with sodiumbicarbonate solution and extracted with ethyl acetate (2×25 ml). Thecombined organic layers were washed with brine (25 ml), dried (MgSO₄)and evaporated. The product was dissolved in 4N HCl/1,4-dioxane andstirred 2 hours. The solid precipitate was filtered on a glass frit,washed with 1,4-dioxane and DCM, and dried under vacuum to leave 150 mg(66%). LC/MS method A: R_(t)=4.13 min., (M+H)⁺=445.

Example 179: Synthesis of2-acetamido-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

A solution of2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamidehydrochloride (15 mg, 38 μmol) and N,N-diisopropylethylamine (17 mg, 132μmol, 24 μl) in N,N-dimethylformamide (0.4 ml) was treated with aceticanhydride (8.0 mg, 76 μmol, 7.5 μl) and stirred 18 hours. Purified byreverse phase HPLC (direct injection of the reaction mixture) and theproduct fractions were evaporated to leave the pure product as a whitesolid (12 mg, 78%). LC/MS method B: R_(t)=1.82 min., (M+H)⁺=405.

Examples 180-184 were prepared on an identical scale and with the samemethod as example 179 above.

Example 180: Synthesis ofN-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)propionamide

N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)propionamidewas prepared according to the procedure of example 179 from2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamidehydrochloride (15 mg, 38 μmol) and propionic anhydride to leave 12 mg(76%). LC/MS method B: R_(t)=1.90 min., (M+H)⁺=419.

Example 181: Synthesis ofN-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)butyramide

N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)butyramidewas prepared according to the procedure of example 179 from2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamidehydrochloride (15 mg, 38 μmol) and butyric anhydride to leave 12 mg(73%). LC/MS method B: R_(t)=1.99 min., (M+H)⁺=433.

Example 182: Synthesis ofN-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)isobutyramide

N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)isobutyramidewas prepared according to the procedure of example 179 from2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamidehydrochloride (15 mg, 38 μmol) and isobutyric anhydride to leave 12 mg(73%). LC/MS method B: R_(t)=1.98 min., purity >95%, (M+H)⁺=433.

Example 183: Synthesis ofN-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)benzamide

N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)benzamidewas prepared according to the procedure of example 179 from2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamidehydrochloride (15 mg, 38 μmol) and benzoic anhydride to leave 14 mg(79%). LC/MS method B: R_(t)=2.10 min., (M+H)⁺=467.

Example 184: Synthesis of2,2,2-trifluoro-N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)acetamide

2,2,2-trifluoro-N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)acetamide was prepared according to theprocedure of example 179 from2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide hydrochloride (15 mg, 38 μmol) and trifluoroacetic anhydrideto leave 13 mg (75%). LC/MS method B: R_(t)=2.12 min., (M+H)⁺=459.

Example 185: Synthesis ofN-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetamideSynthesis of Benzyl (1,1,1-trifluoro-2-methylpropan-2-yl)carbamate

A solution of 1,1,1-trifluoro-2-methylpropan-2-amine (1.0 g, 7.9 mmol,0.90 ml), N,N-diisopropylethylamine (1.5 g, 12 mmol, 1.7 ml) and4-(dimethylamino)pyridine (50 mg) in dichloromethane (40 ml) was cooledin an ice bath and treated with a solution of benzyl chloroformate (2.0g, 12 mmol, 1.7 ml) in dichloromethane (10 ml) dropwise over tenminutes. The mixture was allowed to warm to 20° C. over 2 hours andstirred an additional 24 hours. The mixture was washed with 1N HCl (25ml) and brine (25 ml). The organic phase was dried (MgSO₄) andevaporated. The crude product was purified by chromatography on silicagel eluted with a gradient of ethyl acetate in hexanes (5-10-20%) toleave the product as a solid (1.12 g, 56%). LC/MS method C: R, =2.32min.

Synthesis of tert-butylN-((benzyloxy)carbonyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)glycinate

A solution of benzyl (1,1,1-trifluoro-2-methylpropan-2-yl)carbamate (1.1g, 4.2 mmol) in anhydrous tetrahydrofuran (40 ml) under nitrogenatmosphere in an ice bath was treated with a solution of lithiumhexamethyldisilylamide (1.0 M in tetrahydrofuran, 5.0 ml, 5.0 mmol)dropwise over 15 minutes. The mixture stirred 30 minutes then 1-bromotert-butylacetate (1.2 g, 6.3 mmol, 0.95 ml) was added and the mixturewarmed to 20° C. over 2 hours. Stirring continued for an additional 72hours. The reaction mixture was treated with saturated aqueous ammoniumchloride (5 ml) and stirred 30 mins. Approximately 75% of the solventswere evaporated and the remainder was treated with ethyl acetate (50ml). The mixture was washed with water (25 ml) and brine (25 ml). Theorganic phase was dried (MgSO₄) and evaporated. The crude product waspurified by silica gel chromatography eluting with a gradient of ethylacetate in hexanes (0-30%) to leave the product as an impure mixture(600 mg) which was further purified by reverse phase HPLC to leave theproduct as an oil (165 mg, 10.5%). LC/MS method A: R_(t)=6.57 min.

Synthesis ofN-((benzyloxy)carbonyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)glycine

A solution of tert-butylN-((benzyloxy)carbonyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)glycinate(160 mg, 0.43 mmol) in TFA (2 ml) and DCM (2 ml) was stirred 2 hoursthen evaporated. The residue was dissolved in toluene (5 ml) andevaporated (repeated 2×) to leave 132 mg (97%). LC/MS method A:R_(t)=4.87 min.

Synthesis of benzyl(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)(1,1,1-trifluoro-2-methylpropan-2-yl)carbamate

A solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidemonohydrochloride (150 mg, 0.45 mmol),N-((benzyloxy)carbonyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)glycine(130 mg, 0.41 mmol) and N,N-diisopropylethylamine (120 mg, 0.90 mmol,160 μl) in N,N-dimethylformamide (2 ml) was treated with1-[Bis(dimethylamino) methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (170 mg, 0.45 mmol) and stirred 18 hours. Themixture was diluted with ethyl acetate (50 ml), washed with water (25ml), 1N HCl (25 ml) and brine (25 ml). The organic phase was dried(MgSO₄) and evaporated and the crude product was purified bychromatography on silica gel eluted with a gradient of ethyl acetate inhexanes (20%-70%) to leave the pure product as a gum (188 mg, 76%).LC/MS method A: R_(t)=6.28 min., (M+H)⁺=608.

Synthesis ofN-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetamide

A solution of benzyl(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)(1,1,1-trifluoro-2-methylpropan-2-yl)carbamate(180 mg, 0.30 mmol) in concentrated hydrobromic acid in acetic acid (4ml) stirred for 2 h and a precipitate has formed. The reaction mixturewas diluted with ethyl acetate (50 ml) and washed with aqueous saturatedsodium bicarbonate solution (200 ml). The organic phase was dried(MgSO₄) and evaporated to a solid. Dissolved in 1,4-dioxane (4 ml) andtreated with 4N HCl/1,4-dioxane. The product hydrochloride saltprecipitated and was collected on a medium glass frit, washed withdioxane and dichloromethane, and dried under vacuum to leave the productas a white powder (130 mg, 85%). LC/MS method A: R_(t)=4.45 min.,(M+H)⁺=473.

Example 186: Synthesis of2-(2-oxopiperazin-1-yl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)

A solution of 6-(trifluoromethoxy)benzo[d]thiazol-2-amine (150 mg, 0.64mmol), 2-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)acetic acid (232mg, 0.90 mmol) and N-hydroxybenzotriazole (122 mg, 0.90 mmol) inN,N-dimethylformamide (0.75 ml) was treated with1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (173 mg, 0.90 mmol) andstirred 18 hours. The mixture was diluted with ethyl acetate (25 ml) andwashed with 0.5N HCl (25 ml) and saturated aqueous sodium bicarbonatesolution (25 ml). The organic phase was dried (MgSO₄) and evaporated andthe crude product was purified by silica gel chromatography eluted witha gradient of ethyl acetate in hexanes (0-100%) to leave the pureproduct which was dissolved in ethyl acetate (4 ml) and 4NHCl/1,4-dioxane (6 ml). The mixture stood for 3 hours and theprecipitate was filtered, washed (ethyl acetate) and dries to leave theproduct as a white powder (98 mg, 37%). LC/MS method A: R_(t)=3.60 min.,(M+H)⁺=375.

Example 187: Synthesis of(S)—N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)piperazine-2-carboxamide

A solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidemonohydrochloride (100 mg, 0.293 mmol),(S)-1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (135 mg,0.41 mmol), N-hydroxybenzotriazole (55 mg, 0.41 mmol) and triethylamine(33 mg, 0.32 mmol) in N,N-dimethylformamide (0.50 ml) was treated with1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (79 mg, 0.41 mmol) andstirred 18 hours. The mixture was diluted with ethyl acetate (25 ml) andwashed with 0.5N HCl (25 ml) and saturated aqueous sodium bicarbonatesolution (25 ml). The organic phase was dried (MgSO₄) and evaporated andthe crude product was purified by silica gel chromatography eluted witha gradient of ethyl acetate in hexanes (20-80%) to leave the pureproduct (120 mg) which was dissolved in ethyl acetate (3 ml) and 4NHCl/1,4-dioxane (4 ml). The mixture stood for 3 hours and theprecipitate was filtered, washed (ethyl acetate) and dries to leave theproduct as a white powder (65 mg, 45%). LC/MS method A: R_(t)=3.39 min.,(M+H)⁺=418.

Example 188: Synthesis of(R)—N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)piperazine-2-carboxamide

(R)—N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)piperazine-2-carboxamide was prepared according to the procedure ofexample 187 from2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidemonohydrochloride (100 mg, 0.293 mmol) and(R)-1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid on the samescale as example 187 to provide 60 mg (42%). LC/MS method A: R_(t)=3.39min., (M+H)⁺=418.

Example 189: Synthesis of Benzyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate

To a solution of benzyl 2-hydroxyethylcarbamate (98 mg, 0.5 mmol) inchloroform (1.0 mL) was added triphosgene (60 mg, 0.2 mmol). The mixturewas stirred at 20° C. for 18 hours, then concentrated and dried undervacuum. The residue was dissolved in chloroform (1.0 mL) and was addedto a mixture of 6-(trifluoromethoxy)benzo[d]thiazol-2-amine (117 mg, 0.5mmol) and triethylamine (0.1 ml) in chloroform (2 mL). The resultingmixture was stirred at 20° C. for 18 hours. The mixture was concentratedand the residue was purified by reverse phase HPLC to give the desiredproduct. Yield=54 mg (24%). LC/MS method A: R_(t)=5.87 min.,(M+Na)⁺=478.

Example 190: Synthesis of 2-aminoethyl(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamate

To a solution of benzyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate (32.7 mg, 0.072 mmol) in isopropanol (3 mL) was addedHBr in acetic acid (33%, 0.3 mL). The mixture was heated at 50° C. forovernight, and then concentrated. The residue was purified by reversedHPLC to give the desired product as TFA salt. Yield=28.8 mg (92%). LC/MSmethod A: R_(t)=3.74 min., (M+H)⁺=322.

Example 191: Synthesis of Benzylethyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate

Benzylethyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate was prepared according to the procedure of example 189 at thesame scale from 6-(trifluoromethoxy)benzo[d]thiazol-2-amine and benzylethyl 2-hydroxyethylcarbamate. Yield=23 mg (9.5%). LC/MS method A:R_(t)=5.99 min., (M+H)⁺=484.

Example 192: Synthesis of 2-(Ethylamino)ethyl(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamate

2-(Ethylamino)ethyl (6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamate.was prepared according to the procedure of example 190 at the same scalefrom benzylethyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate(18 mg, 0.037 mmol). Yield=9.5 mg (58%). LC/MS method A: R_(t)=3.89min., (M+H)⁺=350.

Example 193: Synthesis of Benzylmethyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate

Benzylmethyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate was prepared according to the procedure of example 189 at thesame scale from 6-(trifluoromethoxy)benzo[d]thiazol-2-amine and benzylmethyl 2-hydroxyethylcarbamate. Yield=36 mg (15%). LC/MS method A:R_(t)=5.98 min., (M+H)⁺=470.26.

Example 194: Synthesis of 2-(Methylamino)ethyl(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamate

2-(Methylamino)ethyl (6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamatewas prepared according to the procedure of example 190 from benzylmethyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate (18 mg, 0.037 mmol). Yield=19mg (69%). LC/MS method A: R_(t)=3.80 min., (M+H)⁺=336.06.

Example 195: Synthesis of Benzylisopropyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate

Benzylisopropyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate was prepared according to the procedure of example 189 at thesame scale from 6-(trifluoromethoxy)benzo[d]thiazol-2-amine and benzylisopropyl 2-hydroxyethylcarbamate. Yield=51 mg (21%). LC/MS method A:R_(t)=6.79 min., (M+Na)⁺=520.12.

Example 196: Synthesis of 2-(Isopropylamino)ethyl(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)carbamate

2-(Isopropylamino)ethyl(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamate was preparedaccording to the procedure and same scale as example 190 from benzylisopropyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy)ethyl)carbamate. Yield=26 mg (62%). LC/MS method A: R_(t)=3.96 min.,(M+H)⁺=364.

Example 197: Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl(5-(trifluoro methoxy)benzo[d]thiazol-2-yl)carbamate

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl(5-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamate was preparedaccording to the procedure of example 189 at the same scale from6-(trifluoromethoxy)benzo[d]thiazol-2-amine and4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one. Yield=10 mg (5%). LC/MSmethod A: R_(t)=5.67 min.

Example 198: Synthesis of4-amino-2,2-dimethyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamide

4-Amino-2,2-dimethyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butanamidewas prepared according to the procedure of example 147 from2-amino-6-(trifluoromethoxy) benzimidazole (0.10 g, 0.43 mmol) and N-Boc4-amino-2,2-dimethylbutanoic acid (0.15 g, 0.64 mmol). Yield for Bocprotected intermediate 138 mg (72%). LC/MS method A: R_(t)=6.43 min.,purity >90%, (M+H)⁺=448. Yield for final product (111 mg, 100%, 72%overall). LC/MS method A: R_(t)=4.03 min., (M+H)⁺=348.

Example 199: Synthesis of(S)-2-amino-N1,N5-bis(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pentanediamide

(S)-2-amino-N1,N5-bis(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pentanediamidewas prepared according to the procedure of example 147 from2-amino-6-(trifluoromethoxy) benzimidazole (117 mg, 0.5 mmol) and N-Boc(S)-2-aminopentanedioic acid (62 mg, 0.25 mmol). Yield for Boc protectedintermediate 42 mg (25%). LC/MS method A: R_(t)=5.72 min., purity >90%,(M+H)⁺=679. Yield for final product (17 mg, 40%, 10% overall). LC/MSmethod A: R_(t)=4.99 min., (M+H)⁺=580.

Example 200: Synthesis of2-(dimethylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamide

2-(dimethylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl) wasprepared according to the procedure of example 147 from2-amino-6-(trifluoromethoxy) benzimidazole (117 mg, 0.5 mmol) and2-(dimethylamino)acetic acid (58 mg, 0.75 mmol). Yield=200 mg (93%).LC/MS method A: R_(t)=3.35 min., purity >90%, (M+H)⁺=320.

Example 201: Synthesis of1,3-bis(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)urea

A mixture of 2-amino-6-(trifluoromethoxy) benzimidazole (936 mg, 4.0mmol) and triphosgene (593 mg, 2.0 mmol) in chloroform (10 mL) washeated to 60° C. for 18 hours. The solid was filtered off (unreactedriluzole) and filtrate was diluted with ethyl acetate (50 ml), washedwith 1N HCl (25 ml), saturated aqueous NaHCO₃(25 ml) and brine (25 ml),dried over MgSO₄ and concentrated to give the isocyanide intermediate.Yield=375 mg (36%). LC/MS method A: R_(t)=6.41 min., purity >90%,(M+H)⁺=261.19. A mixture of the isocyanide (26 mg, 0.1 mmol) and2-amino-6-(trifluoromethoxy) benzimidazole (23 mg, 0.1 mmol) in2-butanone (0.5 mL) was stirred at 60° C. for 72 hours. The mixture wasconcentrated and the residue was stirred in methylene chloride for 20minutes, the solid was collected, washed with methylene chloride anddried under vacuum. Yield=23 mg (46%). LC/MS method A: R_(t)=6.90 min.,(M+H)⁺=496.

Example 202: Synthesis of Benzyl2-(2-{[(tert-butoxy)carbonyl]amino}acetamido) acetate

A solution of (tert-butyloxycarbonyl)glycine (0.39 g, 2.3 mmol), glycinebenzyl ester hydrochloride (0.50 g, 2.5 mmol) and triethylamine (0.51 g,5.0 mmol, 0.70 ml) in N,N-dimethylformamide (10 ml) was treated withN-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (0.95 g, 2.5 mmol) and stirred 18 hours. Themixture was diluted with ethyl acetate (75 ml) and washed with 1N HCl(50 ml), water (50 ml), 1M sodium carbonate solution (50 ml), water (50ml) and brine (25 ml). The organic phase was dried (MgSO₄) andevaporated to leave benzyl 2-(2-{[(tert-butoxy)carbonyl]amino}acetamido)acetate as a waxy solid (800 mg, 99%). LC/MS method A: R_(t)=4.30 min.,(M+H)⁺=323. ¹H-NMR (CDCl₃): δ=7.36 (s, 5H), 6.55 (bs, 1H), 5.20 (s, 2H),5.09 (bs, 1H), 4.11 (d, J=5.2 Hz, 2H), 3.86 (d, J=5.8 Hz, 2H), 1.46 (s,9H).

Example 203: Synthesis of2-(2-{[(tert-Butoxy)carbonyl]amino}acetamido)acetic acid

Benzyl 2-(2-{[(tert-butoxy)carbonyl]amino}acetamido)acetate (790 mg, 2.4mmol) was hydrogenated at one atmosphere hydrogen pressure over 10% Pd/C(100 mg) in methanol (25 ml) for 18 h. The catalyst was filtered overcelite, washed with methanol (2×5 ml) and the filtrate evaporated underreduced pressure to leave2-(2-{[(tert-butoxy)carbonyl]amino}acetamido)acetic acid as a solid (555mg, 100%). ¹H-NMR (CD₃OD): δ=3.92 (s, 2H), 3.75 (s, 2H), 1.45 (s, 9H).

Example 204: Synthesis of2-Amino-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}acetamide

A solution of2-(methylamino)-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamidedihydrochloride (40 mg, 0.11 mmol), (tert-butyloxycarbonyl)glycylglycine(28 mg, 0.12 mmol) and triethylamine (33 mg, 0.33 mmol, 46 μl) inN,N-dimethylformamide (1 ml) was treated withN-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (44 mg, 0.12 mmol) and the mixture wasstirred for 18 hours. The mixture was then purified by RPHPLC without aworkup procedure (method B) and the product fractions were combined,treated with saturated aqueous sodium bicarbonate solution (50 ml) andextracted with ethyl acetate (2×25 ml). The combined organic phases werewashed with brine (2×25 ml), dried (MgSO₄) and evaporated under reducedpressure to leave a solid (34 mg, 60%). LC/MS method A: R_(t)=4.86 min.,(M+H)⁺=520.

The solid was dissolved in methylene chloride (1 ml) and trifluoroaceticacid (1 ml) and allowed to stand for 2 hours. The solvents wereevaporated and the residue was dissolved in water (25 ml) andlyophilized to leave2-amino-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}acetamide as a light yellow powder trifluoroacetic acidsalt (40 mg, 60% over two steps). LC/MS method A: R_(t)=3.69 min.,(M+H)⁺=420. ¹H-NMR (CD₃OD): δ=7.84 (d, J=1.8 Hz, 1H), 3:1 conformers at7.78 and 7.80 (d, J=8.8 Hz, 1H), 7.35 (dd, J=8.8 Hz, J=1.8 Hz, 1H), 3:1conformers at 4.45 and 4.38 (s, 2H), 3:1 conformers at 4.28 and 4.15 (s,2H), 3.75 (s, 2H), 3:1 conformers at 3.20 and 3.02 (s, 3H).

Example 205: Synthesis of Benzyl2-{[(tert-butoxy)carbonyl](oxan-4-yl)amino}acetate

A solution of 4-aminotetrahydropyran (0.46 g, 4.6 mmol) intetrahydrofuran (10 ml) was treated with triethylamine (0.59 g, 5.8mmol, 0.80 ml) and bromobenzylacetate (1.3 g, 5.8 mmol, 0.91 ml) andstirred for 24 hours. tert-butyloxycarbonyl anhydride (1.0 g, 4.6 mmol)was added and the mixture stirred for 72 hours. The mixture was dilutedwith ethyl acetate (50 ml) and 1N HCl (50 ml) and separated. The organiclayer was washed with water (30 ml), dried (MgSO₄) and evaporated toleave benzyl 2-{[(tert-butoxy)carbonyl](oxan-4-yl)amino}acetate as asolid (0.80 g, 50%). LC/MS method A: R_(t)=5.43 min., (M+H)⁺=250(M+H⁺-100, (t-butyloxcarbonyl)). ¹H-NMR (CDCl₃): δ=7.35 (s, 5H), 5.16(s, 2H), 4.25-4.40 (m, 1H), 3.90-4.01 (m, 2H), 3.84 (s, 2H), 3.44 (t,2H, J=11.7 Hz), 1.33-1.73 (m, 13H).

Example 206: Synthesis of2-{[(tert-Butoxy)carbonyl](oxan-4-yl)amino}acetic acid

A solution of 2-{[(tert-butoxy)carbonyl](oxan-4-yl)amino}acetate (0.80g, 2.3 mmol) was hydrogenated at 1 atmosphere hydrogen pressure over 5%Pd/C (100 mg) in methanol (25 ml) for 2 hours. The mixture was filteredover celite, washed with methanol (2×5 ml) and concentrated to yield2-{[(tert-butoxy)carbonyl](oxan-4-yl)amino}acetic acid as a solid (0.61g, 100%). ¹H-NMR (CDCl₃): δ=conformers at 4.25-4.40 and 3.60-3.80 (m,1H), 3.80-4.05 (m, 4H), 3.45 (t, J=14.3 Hz, 2H), 1.50-1.95 (m, 4H), 1.45(s, 9H).

Example 207: Synthesis of tert-ButylN-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}-N-(oxan-4-yl)carbamate

A solution of 2-{[(tert-butoxy)carbonyl](oxan-4-yl)amino}acetic acid (52mg, 0.15 mmol),2-(methylamino)-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamidedihydrochloride (50 mg, 0.13 mmol) and N,N-diisopropylethylamine (50 mg,0.39 mmol, 70 μl) in N,N-dimethylformamide (1 ml) was treated withN-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (57 mg, 0.15 mmol) and the mixture stirredfor 18 hours. The product mixture was purified by reversed phase HPLC(RPHPLC, method B) without a workup to yield 66 mg (93%) of tert-butylN-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}-N-(oxan-4-yl)carbamateas a solid. LC/MS method A: R_(t)=5.46 min., (M+H)⁺=547.

Example 208: Synthesis ofN-Methyl-2-[(oxan-4-yl)amino]-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamide

A solution of tert-butylN-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}-N-(oxan-4-yl)carbamate(66 mg) in 1,4-dioxane (2 ml) was treated with 4N HCl in 1,4-dioxane (2ml) and the mixture stirred for 2 hours. The product precipitated as afine white powder which was collected by filtration, washed with dioxaneand ether, and dried to yield 56 mg (83%) ofN-methyl-2-[(oxan-4-yl)amino]-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamidedihydrochloride salt. LC/MS method A: R_(t)=3.89 min., (M+H)⁺=447.¹H-NMR (CD₃OD): δ=7.85 (d, J=1.5 Hz, 1H), 3:1 conformers at 7.81 and7.80 (d, J=9.1 Hz, 1H), 7.36 (dd, J=9.1 Hz and J=1.5 Hz, 1H), 4.44 (s,2H), 3:1 conformers at 4.24 and 4.10 (s, 2H), 4.02 (dd, J=12.0 Hz, J=6.5Hz, 2H), 3.35-3.50 (m, 3H), 3:1 conformers at 3.18 and 3.04 (s, 3H),2.20-2.10 (m, 2H), 1.70 (ddd, J=17.0, J=12.4 Hz, J=5.0 Hz, 2H).

Example 209: Synthesis of tert-Butyl3-{[2-(benzyloxy)-2-oxoethyl][(tert-butoxy)carbonyl]amino}azetidine-1-carboxylate

Tert-Butyl 3-{[2-(benzyloxy)-2-oxoethyl][(tert-butoxy)carbonyl]amino}azetidine-1-carboxylate was prepared according to theprocedure for Example 205 from tert-butyl3-aminoazetidine-1-carboxylate. (0.82 g, 42%). LC/MS method A:R_(t)=6.08 min., (M+Na)⁺=423. ¹H-NMR (CDCl₃): δ=7.36 (s, 5H), 5.17 (s,2H), conformers at 4.90-4.50 and 4.35-4.50 (m, 1H), 3.80-4.20 (m, 6H),3.84 (s, 2H), 1.33-1.53 (m, 18H).

Example 210: Synthesis of2-{[(tert-Butoxy)carbonyl]({1-[(tert-butoxy)carbonyl]azetidin-3-yl})amino}aceticacid

2-{[(tert-Butoxy)carbonyl]({1-[(tert-butoxy)carbonyl]azetidin-3-yl})amino}aceticacid was prepared according to the procedure for Example 206 from 0.82 g(2.0 mmol) of tert-butyl3-{[2-(benzyloxy)-2-oxoethyl][(tert-butoxy)carbonyl]amino}azetidine-1-carboxylate(0.64 g, 97%). ¹H-NMR (CDCl₃): δ=conformers at 4.93-5.02 and 4.45-4.53(m, 1H), 3.83-4.22 (m, 6H), 1.44 (s, 18H).

Example 211: Synthesis of tert-Butyl3-{[(tert-butoxy)carbonyl]({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl})amino}azetidine-1-carboxylate

Tert-Butyl3-{[(tert-butoxy)carbonyl]({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl})amino}azetidine-1-carboxylatewas prepared according to the procedure for Example 207 from2-{[(tert-butoxy)carbonyl]({1-[(tert-butoxy)carbonyl]azetidin-3-yl})amino}aceticacid and2-(methylamino)-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamidedihydrochloride (75 mg 94%). LC/MS method A: R_(t)=6.01 min.,(M+H)⁺=618. NMR??

Example 212: Synthesis of2-[(Azetidin-3-yl)amino]-N-methyl-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamide

2-[(Azetidin-3-yl)amino]-N-methyl-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamidewas prepared according to the procedure for Example 208 from tert-butyl3-{[(tert-butoxy)carbonyl]({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl})amino} azetidine-1-carboxylate (75 mg) to yield 43 mg(63%) of2-[(azetidin-3-yl)amino]-N-methyl-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamide as a white powder. LC/MS method A: ¹H-NMR (CD₃OD): δ=7.85 (d,J=1.5 Hz, 1H), 3:1 conformers at 7.81 and 7.80 (d, J=8.8 Hz, 1H), 7.35(dd, J=8.8 Hz and J=1.5 Hz, 1H), 4.20-4.60 (m, 9H), 3:1 conformers at3.21 and 3.18 (s, 3H).

Example 213: Synthesis of tert-Butyl4-{[2-(benzyloxy)-2-oxoethyl][(tert-butoxy)carbonyl]amino}piperidine-1-carboxylate

Tert-Butyl4-{[2-(benzyloxy)-2-oxoethyl][(tert-butoxy)carbonyl]amino}piperidine-1-carboxylatewas prepared according to the procedure for Example 205 from tert-butyl4-aminopiperidine-1-carboxylate. Left tert-butyl4-{[2-(benzyloxy)-2-oxoethyl][(tert-butoxy)carbonyl]amino}piperidine-1-carboxylate(1.3 g, 63%). LC/MS method A: R_(t)=5.43 min., (M+Na)⁺=471. ¹H-NMR(CDCl₃): δ=7.36 (s, 5H), 5.15 (s, 2H), 4.10-4.30 (m, 3H), conformers at3.94 and 3.80 (s, 2H), 2.65-2.80 (m, 2H), 1.70-1.78 (m, 2H), conformersat 1.35-1.45 (s, 18H).

Example 214: Synthesis of2-{[(tert-Butoxy)carbonyl]({1-[(tert-butoxy)carbonyl]piperidin-4-yl})amino}acetic acid

2-{[(tert-Butoxy)carbonyl]({1-[(tert-butoxy)carbonyl]piperidin-4-yl})amino}acetic acid was prepared according to theprocedure for Example 206 from tert-butyl4-{[2-(benzyloxy)-2-oxoethyl][(tert-butoxy)carbonyl]amino}piperidine-1-carboxylate(1.3 g, 2.9 mmol) to provide2-{[(tert-butoxy)carbonyl]({1-[(tert-butoxy)carbonyl]piperidin-4-yl})amino}aceticacid (1.0 g, 96%) as a solid. ¹H-NMR (CDCl₃): δ=4.10-4.32 (m, 3H),3.78-3.95 (m, 2H), 2.65-2.81 (m, 2H), 1.75 (d, J=10.3 Hz, 2H), 1.52 (bs,20H).

Example 215: Synthesis of tert-Butyl4-{[(tert-butoxy)carbonyl]({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl})amino}piperidine-1-carboxylate

Tert-Butyl4-{[(tert-butoxy)carbonyl]({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl})amino}piperidine-1-carboxylate was prepared according to the procedure forExample 207 from2-{[(tert-butoxy)carbonyl]({1-[(tert-butoxy)carbonyl]piperidin-4-yl})amino}aceticacid and2-(methylamino)-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamidedihydrochloride to yield 82 mg (98%) of tert-butyl4{-[(tert-butoxy)carbonyl]({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl})amino}piperidine-1-carboxylate.LC/MS method A: R_(t)=6.20 min., (M+H)⁺=646.

Example 216: Synthesis ofN-Bethyl-2-[(piperidin-4-yl)amino]-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamide

N-Bethyl-2-[(piperidin-4-yl)amino]-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamidewas prepared according to the procedure for Example 208 from tert-butyl4-{[(tert-butoxy)carbonyl]({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl})amino}piperidine-1-carboxylate (82 mg) to yield 57 mg (79%) ofN-methyl-2-[(piperidin-4-yl)amino]-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamideas a white powder. LC/MS method A: R_(t)=3.47 min., (M+H)⁺=447. ¹H-NMR(CD₃OD): δ=7.85 (d, J=2.0 Hz, 1H), 3:1 conformers at 7.81 and 7.80 (d,J=8.8 Hz, 1H), 7.36 (dd, J=8.8 Hz and J=2.0 Hz, 1H), 3:1 conformers at4.45 and 4.47 (s, 2H), 3:1 conformers at 4.32 and 4.18 (s, 2H),3.50-3.61 (m, 3H), 3:1 conformers at 3.20 and 3.05 (s, 3H), 3.12 (ddd,J=13.2 Hz, J=13.2 Hz, J=3.0 Hz, 2H), 2.42 (d, J=13.2 Hz, 2H), 1.95 (ddd,J=20.1 Hz, J=13.2 Hz, J=4.1 Hz, 2H).

Example 217: Synthesis of2-[N-Methyl-2-(morpholin-4-yl)acetamido]-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamide

A solution of 2-(morpholin-4-yl)acetic acid (50 mg, 0.34 mmol),2-(methylamino)-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamidedihydrochloride (106 mg, 0.31 mmol) and DIPEA (88 mg, 0.64 mmol, 122 μl)in N, N-dimethyl formamide (2 ml) was treated withN-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (129 mg, 0.34 mmol) and stirred for 72hours. The mixture was purified by RPHPLC (method B) and the productfractions were combined and lyophilized to leave2-[N-methyl-2-(morpholin-4-yl)acetamido]-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamideas a white powder (92 mg, 54%). LC/MS method A: R_(t)=3.87 min.,(M+H)⁺=433. ¹H-NMR (CD₃OD): δ=7.85 (d, J=1.2 Hz, 1H), 3:1 conformers at7.81 and 7.99 (d, J=9.0 Hz, 1H), 7.36 (dd, J=9.0 Hz, J=1.2 Hz, 1H), 3:1conformers at 4.44 and 4.41 (s, 2H), 3:1 conformers at 4.43 and 4.25 (s,2H), 3.80-4.10 (m, 4H), 3.20-3.60 (m, 4H), 3:1 conformers at 3.16 and3.05 (s, 3H).

Example 218: Synthesis of2-[N-Methyl-2-(piperazin-1-yl)acetamido]-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamide

A solution of 2-{4-[(tert-butoxy)carbonyl]piperazin-1-yl}acetic acid (41mg, 0.17 mmol), 2-(methylamino)-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamide dihydrochloride (50 mg, 0.15 mmol) andN,N-diisopropylethylamine (22 mg, 0.17 mmol, 30 μl) inN,N-dimethylformamide (1 ml) was treated withN-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (65 mg, 0.17 mmol) and stirred 3 hours. Themixture was diluted with ethyl acetate (25 ml) and washed with water (25ml) and brine (25 ml). The organic phase was dried (MgSO₄) andevaporated. The crude product was purified by RPHPLC (method B) and theproduct fractions were combined, treated with saturated aqueous sodiumbicarbonate solution and extracted with ethyl acetate (2×50 ml). Thecombined organic phases were washed with brine (25 ml) and dried(MgSO₄). The solvents were evaporated to leave a colorless glassy solidwhich was dissolved in dichloromethane and trifluoroacetic acid (1:1, 3ml) and allowed to stand for 2 h. The solvents were evaporated and theresidue was dissolved in water (10 ml) and lyophilized to leave2-[N-methyl-2-(piperazin-1-yl)acetamido]-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamideas a white powder (74 mg, 75%). LC/MS method A: R_(t)=3.54 min.,(M+H)⁺=432. ¹H-NMR (CD₃OD): δ=7.86 (d, J=10.3 Hz, 1H), 1:1 conformers at7.81 and 7.99 (d, J=8.8 Hz, 1H), 7.36 (m, 1H), 1:1 conformers at 4.43and 4.38 (s, 2H), 1:1 conformers at 3.71 and 3.40 (s, 2H), 3.35-3.39 (m,2H), 1:1 conformers at 3.20 and 3.08 (s, 3H), 3.00-3.10 (m, 4H),2.68-2.75 (m, 2H).

Example 219: Synthesis of Benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}propanamido]acetate

Benzyl 2-[(2S)-2-{[(tert-butoxy)carbonyl]amino} propanamido]acetate wasprepared according to the procedure for benzyl2-(2-{[(tert-butoxy)carbonyl]amino}acetamido)acetate from(ter-butyloxycarbonyl)alanine to leave benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}propanamido]acetate as a solid.LC/MS method A: R_(t)=5.38 min., (M+H)⁺=337. ¹H-NMR (CDCl₃): δ=7.36 (s,5H), 6.63 (bs, 1H), 5.20 (s, 2H), 4.94 (bs, 1H), 4.21 (q, J=7.0 Hz, 1H),4.09 (ABq, J=5.3 Hz, 2H), 1.45 (s, 9H), 1.37 (d, J=7.0 Hz, 3H).

Example 220: Synthesis of2-[(2S)-2-{[(tert-Butoxy)carbonyl]amino}propanamido]acetic acid

Benzyl 2-[(2S)-2-{[(tert-butoxy)carbonyl]amino} propanamido]acetate wasprepared according to the procedure for benzyl2-(2-{[(tert-butoxy)carbonyl]amino}acetamido)acetate from Benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}propanamido]acetate to provide2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}propanamido]acetic acid as asolid. ¹H-NMR (CDCl₃): δ=4.10 (q, J=7.3 Hz, 1H), 3.90 (ABq, J=17.9 Hz,2H), 1.44 (s, 9H), 1.32 (d, J=7.0 Hz, 3H).

Example 221: Synthesis of(2S)-2-Amino-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}propanamide

(2S)-2-Amino-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}propanamidewas prepared according to the procedure for2-amino-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}acetamidefrom (tert-butyloxycarbonyl)alanylglycine to provide(25)-2-amino-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}propanamideLC/MS method A: R_(t)=3.72 min., (M+H)⁺=434. ¹H-NMR (CD₃OD): δ=7.84 (d,J=1.8 Hz, 1H), 3:1 conformers at 7.78 and 7.80 (d, J=8.7 Hz, 1H), 7.35(dd, J=8.7 Hz, J=1.8 Hz, 1H), 3:1 conformers at 4.46 and 4.38 (s, 2H),4.26 (ABq, J=17.3 Hz, 2H), 4.00 (q, J=7.0 Hz, 1H), 3:1 conformers at3.20 and 3.02 (s, 3H), 1.52 (d, J=7.0 Hz, 3H).

Example 222: Synthesis of Benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-phenyl propanamido]acetate

Benzyl 2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-phenylpropanamido]acetate was prepared according to the procedure for benzyl2-(2-{[(tert-butoxy)carbonyl]amino}acetamido)acetate from(tert-butyloxycarbonyl)phenylalanine to provide benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-phenylpropanamido]acetate.LC/MS method A: R_(t)=5.38 min., (M+Na)⁺=435. ¹H-NMR (CDCl₃):δ=7.18-7.40 (m, 10H), 6.37 (bs, 1H), 5.17 (s, 2H), 4.92 (bs, 1H), 4.03(ABq, J=18.5 Hz, J=5.6 Hz, 1H), (ABq, J=18.4 Hz, J=5.0 Hz, 1H), 3.10(doublet of ABq, J=14.0 Hz, J=6.7 Hz, J=4.7 Hz, 2H), 1.40 (s, 9H).

Example 223: Synthesis of2-[(2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-phenylpropanamido]acetic acid

2-[(2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-phenylpropanamido]acetic acidwas prepared according to the procedure for2-(2-{[(tert-butoxy)carbonyl]amino}acetamido)acetic acid from Benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-phenylpropanamido]acetate toprovide2-[(2S)-2-[(tert-butoxy)carbonyl]amino-3-phenylpropanamido]acetic acidas a solid. ¹H-NMR (CD₃OD): δ=7.18-7.30 (m, 5H), 4.34 (dd, J=9.7 Hz,J=5.3 Hz, 1H), 3.91 (s, 2H), 3.17 (dd, J=13.7 Hz, J=4.7 Hz, 1H), 2.80(dd, J=13.7 Hz, J=9.7 Hz, 1H), 1.34 (s, 9H).

Example 224: Synthesis of(2S)-2-Amino-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}-3-phenylpropanamide

(2S)-2-Amino-N-{[methyl([{6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}-3-phenylpropanamidewas prepared according to the procedure for2-amino-N-{[methyl([{6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}acetamidefrom (tert-butyloxycarbonyl)phenylalanylglycine. LC/MS method A:R_(t)=4.19 min., (M+H)⁺=510. ¹H-NMR (CD₃OD): δ=7.85 (bs, 1H), 3:1conformers at 7.81 and 7.79 (d, J=7.4 Hz, J=8.8 Hz, 1H), 7.27-7.40 (m,6H), 3:1 conformers at 4.45 and 4.38 (s, 2H), 3:1 conformers at 4.22 and4.10 (ABq, J=17.3 Hz, J=15.0 Hz, 2H), 4.15 (obscured dd, 1H), 3.12(obscured dd, 1H), 3:1 conformers at 3.20 and 3.02 (s, 3H), 3.04(obscured dd, 1H).

Example 225: Synthesis of Benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-methyl butanamido]acetate

A solution of (tert-butyloxycarbonyl)valine succinate ester (0.71 g, 2.3mmol) and glycine benzyl ester hydrochloride (0.50 g, 2.5 mmol) inN,N-dimethylformamide (10 ml) was treated with triethylamine (0.51 g,5.0 mmol, 0.70 ml) and stirred 18 hours. A white precipitate formed. Themixture was diluted with ethyl acetate (75 ml) and washed with 1N HCl(50 ml), water (50 ml) and brine (25 ml). The organic phase was dried(MgSO₄) and evaporated to leave benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-methylbutanamido]acetate as awaxy solid (829 mg, 100%). LC/MS method A: R_(t)=5.03 min., (M+Na)⁺=387.¹H-NMR (CDCl₃): δ=7.36 (s, 5H), 6.45 (bs, 1H), 5.19 (s, 2H), 5.00 (bs,1H), 4.10 (dd, J=5.3 Hz, J=2.6 Hz, 2H), 3.00 (dd, J=7.2 Hz, J=5.6 Hz,1H), 2.15-2.25 (m, 1H), 1.45 (s, 9H), 0.98 (d, J=6.8 Hz, 3H), 0.92 (d,J=7.1 Hz, 3H).

Example 226: Synthesis of2-[(2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-methyl butanamido]acetic acid

2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-methylbutanamido]acetate(0.82 g, 2.2 mmol) was hydrogenolyzed (1 atmosphere hydrogen pressure)in methanol (25 ml) over 5% Pd/C (100 mg) for 18 hours. The catalyst wasfiltered through a bed of celite, washed with methanol (2×5 ml) and thefiltrate was evaporated under reduced pressure to afford2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-methylbutanamido]acetic acidas a solid (636 mg, 100%). ¹H-NMR (CD₃OD): δ=8.20 (bs, 1H), 3.80-4.03(m, 3H), 2.00-2.15 (m, 1H), 1.44 (s, 9H), 0.97 (d, J=6.8 Hz, 3H), 0.93(d, J=6.8 Hz, 3H).

Example 227: Synthesis of(2S)-2-Amino-3-methyl-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}butanamide

(2S)-2-Amino-3-methyl-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}butanamidewas prepared according to the procedure for2-amino-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl} acetamide from (tert-butyloxycarbonyl)valylglycine.LC/MS method A: R_(t)=3.91 min., (M+H)⁺=462. ¹H-NMR (CD₃OD): δ=7.84 (d,J=1.2 Hz, 1H), 3:1 conformers at 7.79 and 7.80 (d, J=8.8 Hz, 1H), 7.35(dd, J=8.8 Hz, J=1.2 Hz, 1H), 3:1 conformers at 4.46 and 4.39 (s, 2H),3:1 conformers at 4.28 and 4.15 (ABq, J=10.0 Hz, J=4.7 Hz, 2H), 3:1conformers at 4.15 and 3.71 (d, J=5.9 Hz, 1H), 3:1 conformers at 3.20and 3.02 (s, 3H), 2.15-2.25 (m, 1H), 1.07 (d, J=6.8 Hz, 3H), 1.06 (d,J=7.0 Hz, 3H).

Example 228: Synthesis of Benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]acetate

Benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]acetate wasprepared according to the procedure for benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-methylbutanamido]acetate from(tert-butyloxycarbonyl)leucine succinate ester to provide benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]acetate asan oil. LC/MS method A: R_(t)=5.32 min., (M+Na)⁺=401. ¹H-NMR (CDCl₃):δ=7.36 (s, 5H), 6.61 (bs, 1H), 5.18 (s, 2H), 4.84 (bd, J=8.5 Hz, 1H),4.15 (bs, 1H), 4.08 (d, J=5.2 Hz, 2H), 1.65-1.75 (m, 3H), 1.44 (s, 9H),0.95 (d, J=6.1 Hz, 3H), 0.92 (d, J=6.1 Hz, 3H).

Example 229: Synthesis of2-[(2S)-2-{[(tert-Butoxy)carbonyl]amino}-4-methyl pentanamido]aceticacid

2-[(2S)-2-[(tert-Butoxy)carbonyl]aminol-4-methyl pentanamido]acetic acidwas prepared according to the procedure for2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-methylbutanamido]acetic acidfrom Benzyl2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]acetate toprovide 2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]acetic acid as asolid. ¹H-NMR (CD₃OD): δ=4.11 (dd, J=10.4 Hz, J=5.0 Hz, 1H), 3.90 (ABq,J=17.9 Hz, 2H), 1.50-1.80 (m, 3H), 1.44 (s, 9H), 0.95 (d, J=6.4 Hz, 3H),0.93 (d, J=6.2 Hz, 3H).

Example 230: Synthesis of(2S)-2-Amino-4-methyl-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}pentanamide

(2S)-2-Amino-4-methyl-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}pentanamidewas prepared according to the procedure for2-amino-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}acetamidefrom (tert-butyloxycarbonyl)leucylglycine. LC/MS method A: R_(t)=4.09min., (M+H)⁺=476. ¹H-NMR (CD₃OD): δ=7.84 (d, J=2.1 Hz, 1H), 3:1conformers at 7.79 and 7.77 (d, J=8.8 Hz, J=7.2 Hz, 1H), 7.35 (dm, J=7.8Hz, 1H), 3:1 conformers at 4.46 and 4.38 (s, 2H), 3:1 conformers at 4.26and 4.13 (ABq, J=15.2 Hz, J=9.1 Hz, 2H), 3.93 (dd, J=7.6 Hz, J=6.2 Hz,1H), 3:1 conformers at 3.20 and 3.02 (s, 3H), 1.65-1.80 (m, 3H), 1.01(d, J=5.6 Hz, 3H), 0.99 (d, J=5.0 Hz, 3H).

Example 231: Synthesis of Benzyl 2-[(oxetan-3-yl)amino]acetate

A solution of 4-aminooxetane (300 mg, 4.1 mmol) and benzyl2-bromoacetate (1.3 g, 5.8 mmol, 0.91 ml) in acetonitrile (10 ml) wasstirred 72 hours. The mixture was diluted with 1N HCl (50 ml) andextracted with ethyl acetate (50 ml). The aqueous layer was neutralized(pH=9) with solid sodium carbonate and extracted with ethyl acetate(2×50 ml). The combined organic layers were washed with brine, dried(MgSO₄) and evaporated under reduced pressure to leave benzyl2-[(oxetan-3-yl)amino]acetate as an oil (160 mg, 17%). ¹H-NMR (CDCl₃):δ=7.36 (m, 5H), 5.16 (s, 2H), 4.76 (t, J=7.0 Hz, 2H), 4.48 (t, J=6.4 Hz,2H), 3.92-4.01 (m, 1H), 3.45 (s, 2H).

Example 232: Synthesis of Benzyl2-{[(tert-butoxy)carbonyl](oxetan-3-yl)amino}acetate

A solution of 2-[(oxetan-3-yl)amino]acetate (155 mg, 0.66 mmol) inmethylene chloride (5 ml) was treated with tert-butyloxycarbonylanhydride (168 mg, 0.79 mmol) and stirred 18 hours. The solvents wereevaporated and the residue was purified by chromatography on silica geleluted with a gradient of ethyl acetate in hexanes (10% to 20% to 40%)to leave benzyl 2-{[(tert-butoxy)carbonyl](oxetan-3-yl)amino}acetate asa colorless oil (200 mg, 90%). LC/MS method A: R_(t)=5.13 min. ¹H-NMR(CDCl₃): δ=7.36 (bs, 5H), 1:1 conformers at 5.22-5.35 and 4.90-5.00 (m,1H), 5.18 (s, 2H), 4.58-4.85 (m, 4H), 4.12 (s, 2H), 1:1 conformers at1.45 and 1.37 (s, 9H).

Example 233: Synthesis of2-{[(tert-Butoxy)carbonyl](oxetan-3-yl)amino}acetic acid

2-{[(tert-butoxy)carbonyl](oxetan-3-yl)amino}acetate (195 mg, 0.58 mmol)was hydrogenated (1 atmosphere hydrogen pressure) over 10% Pd/C (30 mg)in methanol (5 ml) for 18 hours. The catalyst was filtered and washedwith methanol (2×5 ml) and the filtrate was evaporated to leave2-{[(tert-butoxy)carbonyl](oxetan-3-yl)amino}acetic acid as a whitesolid (135 mg, 100%). ¹H-NMR (CDCl₃): δ=1:1 conformers at 5.22-5.35 and4.90-5.05 (m, 1H), 4.60-4.90 (m, 4H), 4.12 (s, 2H), 1.45 (s, 9H).

Example 234: Synthesis ofN-Methyl-2-[(oxetan-3-yl)amino]-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamide

A solution of 2-{[(tert-butoxy)carbonyl](oxetan-3-yl)amino}acetic acid(30 mg, 0.13 mmol),2-(methylamino)-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamidedihydrochloride (40 mg, 0.12 mmol) and triethylamine (26 mg, 0.26 mmol,36 μl) in N,N-dimethylformamide (1 ml) was treated withN-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (49 mg, 0.13 mmol) and stirred 18 hours. Theproduct was purified by reversed phase HPLC (method B) and the productfractions were combined, treated with saturated sodium bicarbonatesolution (50 ml) and extracted with ethyl acetate (2×50 ml). Thecombined organic phases were washed with brine (25 ml), dried (MgSO₄)and evaporated to a thick gum (47 mg, 76%). This was dissolved in 4N HClin 1,4-dioxane (3 ml) and stirred for 2 hours. The solvents wereevaporated and the residue was dissolved in water (8 ml) andacetonitrile (2 ml) and lyophilized to leave a white powder (36 mg, 56%over two steps). LC/MS method A: R_(t)=4.23 min., (M+H)⁺=419. ¹H-NMR(CD₃OD): δ=7.85 (bs, 1H), 3:1 conformers at 7.81 and 7.79 (d, J=7.9 Hz,J=8.8 Hz, 1H), 7.35 (dm, J=7.9 Hz, 1H), 4.00-4.50 (m, 7H), 3:1conformers at 3.20 and 3.02 (s, 3H).

Example 235: Synthesis of (2,2,2-Trifluoro-ethylamino)-acetic acid ethylester

A flask was charged with 2,2,2-Trifluoroethylamine hydrochloride (2.81g, 20.7 mmol) and potassium iodide (340 mg, 2.07 mmol). DIEA (14.5 mL)was added to the flask and the mixture was stirred for 5 minutes beforeadding ethyl bromoacetate (3.46 g, 20.7 mmol, 2.3 mL). The slurry wasstirred overnight at room temperature. The slurry was diluted withdiethyl ether (75 mL) and stirred for 1 hour. The reaction mixture wasfiltered and the filtrate was concentrated in vacuo. The crude residuewas dissolved in methylene chloride (30 mL) and extracted into 1N HCl(2×30 mL). The aqueous layer was neutralized with sat. aqueous NaHCO₃and the product was extracted with methylene chloride (3×30 mL). Thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated in vacuo to provide (2,2,2-Trifluoro-ethylamino)-aceticacid ethyl ester as a brown oil. ¹H NMR (300 MHz, CDCl₃) δ=4.27-4.14 (m,2H), 3.56-3.48 (m, 2H), 3.31-3.17 (m, 2H), 1.29 (t, J=7.0 Hz, 3H)

Example 236: Synthesis of[(2-Chloro-acetyl)-(2,2,2-trifluoro-ethyl)-amino]-acetic acid ethylester

Chloroacetyl chloride (358 mg, 3.17 mmol, 252 μL) was added dropwise toa solution of (2,2,2-trifluoro-ethylamino)-acetic acid ethyl ester (489mg, 2.64 mmol) and diisopropylethylamine (751 mg, 5.81 mmol, 1.01 mL) indichloromethane (13 mL) at 0° C., keeping the temperature <5° C. duringthe addition. The mixture was stirred for 30 minutes then quenched with1N HCl (13 mL). The layers were separated and the aqueous layer wasextracted with methylene chloride (2×13 mL). The combined organicextracts were dried over Na₂SO₄, filtered, and concentrated in vacuo togive 672 mg (97%) of ethyl[(2-Chloro-acetyl)-(2,2,2-trifluoro-ethyl)-amino]-acetate as a brownoil. ¹H NMR (300 MHz, CDCl₃) δ=4.45-3.99 (m, 8H), 1.37-1.24 (m, 3H)

Example 237: Synthesis of[(2-tert-Butylamino-acetyl)-(2,2,2-trifluoro-ethyl)-amino]-acetic acidethyl ester

tert-Butylamine (296 mg, 4.05 mmol, 426 μL) was added to a solution of[(2-chloro-acetyl)-(2,2,2-trifluoro-ethyl)-amino]-acetic acid ethylester (265 mg, 1.01 mmol) and diisopropylethylamine (131 mg, 1.01 mmol,176 μL) in dichloromethane (5 mL) and the reaction was stirredovernight. The product was extracted into 1N HCl (2×10 mL). The aqueouslayer was neutralized with sat. aqueous NaHCO₃ and the product wasextracted with methylene chloride (3×10 mL). The combined organicextracts were dried over Na₂SO₄, filtered, and

concentrated in vacuo to 130 mg (43%) of[(2-tert-butylamino-acetyl)-(2,2,2-trifluoro-ethyl)-amino]-acetic acidethyl ester as a brown oil. ¹H NMR (300 MHz, CDCl₃) δ=4.22 (d, J=17.6Hz, 4H), 4.17-4.02 (m, 2H), 3.56-3.35 (m, 2H), 1.36-1.24 (m, 3H), 1.10(d, J=5.0 Hz, 9H)

Example 238: Synthesis of2-tert-Butylamino-N-(2,2,2-trifluoro-ethyl)-N-[(6-trifluoromethoxy-benzothiazol-2-ylcarbamoyl)-methyl]-acetamide

Sodium ethoxide (45 mg, 0.65 mmol) was added to a stirred solution of2-amino-6-(trifluoromethoxy)benzothiazole (102 mg, 0.44 mmol) in ethanol(2.5 mL) at room temperature. After stirring for 10 minutes, a solutionof [(2-tert-butylamino-acetyl)-(2,2,2-trifluoro-ethyl)-amino]-aceticacid ethyl ester (130 mg, 0.44 mmol) in ethanol (1 mL) was added. Themixture was stirred overnight. The reaction was quenched with water (500μL) then concentrated to dryness in vacuo. The residue was diluted withN,N-dimethylformamide and purified by prep HPLC (method B). The purifiedproduct was freeze dried from dioxane to obtain 97 mg (37%) of thetrifluoroacetic acid salt of2-tert-butylamino-N-(2,2,2-trifluoro-ethyl)-N-[(6-trifluoromethoxy-benzothiazol-2-ylcarbamoyl)-methyl]-acetamideas a white powder. LC/MS method A: R_(t)=4.42 min., (M+H)⁺=487. 1H NMR(300 MHz, DMSO-d6) δ=12.91-12.56 (m, 1H), 9.08-8.63 (m, 2H), 8.32-7.97(m, 1H), 7.93-7.75 (m, 1H), 7.54-7.25 (m, 1H), 4.69-4.52 (m, 2H),4.49-4.32 (m, 2H), 4.13-3.95 (m, 2H), 1.38-1.19 (m, 9H).

Example 239: Synthesis of Benzyl2-{[(tert-butoxy)carbonyl](cyclohexyl)amino} acetate

A solution of benzyl 2-bromoacetate (1.3 g, 5.8 mmol), cyclohexylamine(456.5 mg, 4.6 mmol) and triethylamine (0.59 g, 5.8 mmol) intetrahydrofuran (10 mL) was stirred 18 h. Di-tert-butyl dicarbonate (1g, 4.6 mmol) was added and the reaction stirred for 24 hours. Ethylacetate (100 ml) was added and the mixture was washed with water (2×50ml), 1N HCl (50 ml), and brine (25 ml). The organic solution was driedover sodium sulfate and evaporated to give a crude product. Purificationby silica gel chromatography afforded benzyl2-{[(tert-butoxy)carbonyl](cyclohexyl)amino}acetate as a colorless oil(1.03 g, 65%). LC/MS method A: R_(t)=6.44 min., (M+H)⁺-100(t-butoxycarbonyl)=248. ¹H NMR (300 MHz, CDCl₃): δ 7.40-7.24 (m, 5H),5.15 (s, 2H), 4.03-3.95 (m, 1H), 3.82 (s, 2H), 1.77-1.74 (m, 4H),1.47-1.44 (m, 2H), 1.34 (s, 9H), 1.31-1.17 (m, 4H).

Example 240: Synthesis of2-{[(tert-Butoxy)carbonyl](cyclohexyl)amino}acetic acid

Benzyl 2-{[(tert-butoxy)carbonyl](cyclohexyl)amino}acetate (1.035 g,2.98 mmol) in methanol (20 mL) was hydrogenated (1 atmosphere H₂pressure) over Pd/C (100 mg) for 18 hours. The mixture was filteredthrough celite and the filtrate was evaporated to give2-{[(tert-butoxy)carbonyl](cyclohexyl)amino}acetic acid as a white solid(0.75 g, 98%). LC/MS method A: R_(t)=5.20 min., (M+Na)⁺=280. ¹H NMR (300MHz, CDCl₃): δ 4.03-3.84 (m, 3H), 1.81-1.61 (m, 4H), 1.44 (s, 9H),1.43-1.07 (m, 6H).

Example 241: Synthesis of2-(Cyclohexylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide

To a solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidedihydrochloride (50 mg, 0.13 mmol),2-{[(tert-butoxy)carbonyl](cyclohexyl)amino}acetic acid (38.6 mg, 0.15mmol) and N,N-diisopropylethylamine (50 mg, 0.39 mmol, 70 μl) inN,N-dimethylformamide (1 ml) was added1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 57 mg, 0.15 mmol) and the reactionmixture stirred for 18 hours. The crude material was purified via RPHPLC(method B) to give a light yellow foamy solid (LC/MS method A;R_(t)=6.07 min., (M+Na)⁺=566.6). The solid was dissolved in 4N HCl in1,4-dioxane. The mixture stirred 18 h and the white precipitate wasfiltered on a glass frit (medium), washed with 1,4-dioxane and ether anddried under vacuum to leave2-(cyclohexylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamideas a white crystalline solid (49.1 mg, 70%). LC/MS method A: R_(t)=4.00min., (M+H)⁺=445. ¹H NMR (300 MHz, CD₃OD): δ 7.96-7.73 (m, 2H), 7.36 (d,J=8.80 Hz, 1H), 4.43 (s, 2H), 4.20 (s, 2H), 3.17 (s, 3H), 3.04 (m, 1H),2.13 (m, 2H), 1.89 (m, 2H), 1.72 (d, J=11.73 Hz, 1H), 1.49-1.20 (m, 5H).

Example 242: Synthesis of Benzyl2-{[(tert-butoxy)carbonyl](1-methanesulfonylpiperidin-4-yl)amino}acetate

A mixture of benzyl 2-bromoacetate (1.3 g, 5.8 mmol),4-Amino-1-methanesulfonylpiperidine (820 mg, 4.6 mmol) and triethylamine(0.59 g, 5.8 mmol) in tetrahydrofuran (10 mL) was stirred for 18 hours.Di-tert-butyl dicarbonate (1 g, 4.6 mmol) was added and the mixturestirred for another 20 hours. Ethyl acetate (100 ml) was added and themixture was washed with water (2×50 ml), 1N HCl (50 ml), and brine (25ml). The organic solution was dried over sodium sulfate and evaporatedto give a crude product which was purified by chromatography on silicagel to give benzyl 2-{[(tert-butoxy)carbonyl](1-methanesulfonylpiperidin-4-yl)amino}acetate as a colorless oil (1.56 g, 79.5%). LC/MSmethod A: R_(t)=5.24 min., (M+H)⁺-100 (t-butyloxycarbonyl)=327. ¹H NMR(300 MHz, CDCl₃): δ 7.36 (s, 5H), 5.16 (s, 2H), 3.97-3.87 (m, 1H), 3.82(s, 2H), 2.78 (s, 3H), 2.77-2.68 (m, 2H), 1.89-1.85 (m, 2H), 1.71-1.61(m, 2H), 1.48-1.45 (m, 2H), 1.35 (s, 9H).

Example 243: Synthesis of2-{[(tert-Butoxy)carbonyl](1-methanesulfonylpiperidin-4-yl)amino}aceticacid

Benzyl2-{[(tert-butoxy)carbonyl](1-methanesulfonylpiperidin-4-yl)amino}acetate(1.56 g, 3.66 mmol) was hydrogenated (1 atmosphere hydrogen pressure) inmethanol (20 mL) over Pd/C (100 mg) for 20 hours. The mixture wasfiltered through celite and evaporated to give2-{[(tert-butoxy)carbonyl](1-methanesulfonylpiperidin-4-yl)amino}aceticacid as a white solid (0.97 g, 79%). LC/MS method A: R_(t)=3.37 min.,(M+Na)⁺=359. ¹H NMR (300 MHz, CDCl₃): δ 3.88-3.84 (m, 1H), 3.81 (s, 2H),2.80 (s, 3H), 2.76-2.71 (m, 2H), 1.90-1.87 (m, 2H), 1.64-1.60 (m, 2H),1.59-1.45 (m, 2H), 1.43 (s, 9H).

Example 244: Synthesis of2-[(1-Methanesulfonylpiperidin-4-yl)amino]-N-methyl-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamide

To a solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidedihydrochloride (50 mg, 0.13 mmol),2-{[(tert-butoxy)carbonyl](1-methanesulfonylpiperidin-4-yl)amino}aceticacid (50.46 mg, 0.15 mmol) and N,N-diisopropylethylamine (50 mg, 0.39mmol, 70 μl) in N,N-dimethylformamide (1 ml) was added1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 57 mg, 0.15 mmol) and the reactionmixture stirred for 18 hours. The crude mixture was purified by RPHPLC(method B) and the product fractions were evaporated to give a lightyellow foamy solid (LC/MS, method A; R_(t)=5.12 min., (M+Na)⁺=646). Thesolid was dissolved in 4N HCl in 1,4-dioxane. The mixture stirredovernight and the white precipitate was filtered on a glass frit(medium), washed with 1,4-dioxane and ether and dried under vacuum toleave 61.1 mg (59%) of2-[(1-methanesulfonylpiperidin-4-yl)amino]-N-methyl-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamideas a white crystalline solid. LC/MS method A: R_(t)=3.72 min.,(M+H)⁺=524. ¹H NMR (300 MHz, CD₃OD): δ 7.95-7.70 (m, 2H), 7.36 (d,J=8.21 Hz, 1H), 4.44 (s, 2H), 4.34-4.06 (m, 2H), 3.87 (d, J=12.31 Hz,2H), 3.36 (m, 1H), 3.18 (s, 3H), 2.87 (s, 3H), 2.81 (m, 2H), 2.25 (d,J=9.97 Hz, 2H), 1.88-1.55 (m, 2H)

Example 245: Synthesis of tert-Butyl N-(2-amino-2-methylpropyl)carbamate

A mixture of 2-methylpropane-1,2-diamine (1.1 g, 12.5 mmol) indichloromethane (10 mL) was cooled to 0° C., Di-tert-butyl dicarbonate(2.7 g, 12.5 mmol) was added and the mixture was stirred 20 hours. Thesolvent was evaporated to give tert-butylN-(2-amino-2-methylpropyl)carbamate as a white solid (2.4 g, 100%) whichwas used directly for the next step without characterization. LC/MSmethod A: R_(t)=3.70 min., (M+H)⁺=327. ¹H NMR (300 MHz, CDCl₃): δ7.38-7.27 (m, 5H), 5.17 (s, 2H), 3.41 (s, 2H), 3.01-2.99 (d, J=5.8 Hz,2H), 1.44 (s, 9H), 1.24 (s, 6H).

Example 246: Synthesis of Benzyl2-{[(tert-butoxy)carbonyl](1-{[(tert-butoxy)carbonyl]amino}-2-methylpropan-2-yl)amino}acetate

A mixture of benzyl 2-bromoacetate (3.04 g, 13 mmol), tert-butylN-(2-amino-2-methylpropyl)carbamate (2.5 g, 13 mmol), triethylamine (1.7g, 16 mmol) in tetrahydrofuran (15 mL) was stirred 18 h.Di-tert-butyldicarbonate (2.8 g, 13 mmol) was added and the mixturestirred for another 24 hours. Ethyl acetate (100 ml) was added and themixture was washed with water (2×50 ml), 1N HCl (50 ml), and brine (25ml). The organic solution was dried over sodium sulfate and evaporatedto give a crude product which was purified by silica gel chromatographyelute with a hexanes/ethyl acetate gradient to give benzyl2-{[(tert-butoxy)carbonyl](1-{[(tert-butoxy)carbonyl]amino}-2-methylpropan-2-yl)amino}acetateas a colorless oil (1.27 g, 23%) along with amine starting material(0.74 g, 17%). LC/MS method A: R_(t)=6.26 min., (M+Na)⁺=459. ¹H NMR (300MHz, CD₃OD): δ 7.40-7.31 (m, 5H), 5.19 (s, 2H), 4.07 (s, 2H), 3.46 (s,2H), 1.42 (s, 9H), 1.35 (s, 6H), 1.32 (s, 9H).

Example 247: Synthesis of2-{[(tert-Butoxy)carbonyl](1-{[(tert-butoxy)carbonyl]amino}-2-methylpropan-2-yl)amino}aceticacid

Benzyl2-{[(tert-butoxy)carbonyl](1-{[(tert-butoxy)carbonyl]amino}-2-methylpropan-2-yl)amino}acetate(178 mg, 0.41 mmol) in methanol (20 mL) was hydrogenated (1 atmospherehydrogen pressure) over Pd/C (50 mg) for 20 hours. The mixture wasfiltered through celite and evaporated to give2-{[(tert-butoxy)carbonyl](1-{[(tert-butoxy)carbonyl]amino}-2-methylpropan-2-yl)amino}aceticacid as a colorless oil (161 mg, 100%). LC/MS method A: R_(t)=4.7 min.,(M+Na)⁺=369.

Example 248: Synthesis of2-[(1-Amino-2-methylpropan-2-yl)amino]-N-methyl-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamide

To a solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidedihydrochloride (51.68 mg, 0.14 mmol),2-{[(tert-butoxy)carbonyl](1-{[(tert-butoxy)carbonyl]amino}-2-methylpropan-2-yl)amino}aceticacid (52 mg, 0.15 mmol) and N,N-diisopropylethylamine (53 mg, 0.41 mmol,70 μl) in N,N-dimethylformamide (1 ml) was added1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 57 mg, 0.15 mmol) and the reactionmixture stirred for 18 hours. The crude product was purified by RPHPLC(method B) to give a light yellow foamy solid (LC/MS method A, R_(t)=6.0min., (M+H)⁺=634.33). This was dissolved in 4N HCl in 1,4-dioxane. Themixture was stirred 20 hours and the white precipitate was filtered on aglass frit (medium), washed with 1,4-dioxane and ether and dried undervacuum to leave 49 mg (72%) of2-[(1-amino-2-methylpropan-2-yl)amino]-N-methyl-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamideas a white crystalline solid. LC/MS method A: R_(t)=3.27 min.,(M+H)⁺=434. ¹H NMR (300 MHz, CD₃OD): δ 7.93-7.73 (m, 2H), 7.36 (d,J=8.21 Hz, 1H), 4.55-4.42 (m, 2H), 4.36-4.16 (m, 2H), 3.37 (m, 2H), 3.22(s, 3H), 1.60-1.49 (m, 6H).

Example 249: Synthesis of tert-Butyl4-{[2-(benzyloxy)-2-oxoethyl](methyl)amino} piperidine-1-carboxylate

A mixture of benzyl 2-bromoacetate (1.3 g, 5.8 mmol),1-(tert-butyloxcarbonyl)-4-(methylamino)piperidine (1.24 g, 5.8 mmol)and triethylamine (0.59 g, 5.8 mmol) in tetrahydrofuran (10 mL) wasstirred overnight. Water (50 ml) was added followed by ethyl acetateextraction 2×100 ml). The organic solution was dried over sodium sulfateand evaporated to give a crude product which was purified bychromatography on silica gel using a gradient of ethyl acetate inhexanes to give tert-butyl 4-[2-(benzyloxy)-2-oxoethyl](methyl)aminopiperidine-1-carboxylate as a colorless oil (1.87 g, 84%). LC/MS methodA: R_(t)=3.76 min., (M+Na)⁺=385. ¹H NMR (300 MHz, CDCl₃): δ 7.34 (m,5H), 5.14 (s, 2H), 4.11-4.09 (m, 2H), 3.37 (s, 2H), 2.68-2.60 (m, 3H),2.40 (s, 3H), 1.79-1.74 (m, 2H), 1.43 (s, 9H), 1.36-1.31 (m, 2H).

Example 250: Synthesis of2-({1-[(tert-Butoxy)carbonyl]piperidin-4-yl}(methyl)amino) acetic acid

tert-Butyl4-{[2-(benzyloxy)-2-oxoethyl](methyl)amino}piperidine-1-carboxylate(1.87 g, 5.17 mmol) in methanol (20 mL) was hydrogenated (one atmospherehydrogen pressure) over Pd/C (150 mg) for 18 hours. The mixture wasfiltered through celite and the filtrate was evaporated to give2-({1-[(tert-butoxy)carbonyl]piperidin-4-yl}(methyl)amino)acetic acid asa colorless oil (1.365 g, 97%). LC/MS method A: R_(t)=2.62 min.,(M+H)⁺=273. ¹H NMR (300 MHz, CDCl₃): δ 4.25 (m, 2H), 3.45 (s, 2H),3.38-3.30 (m, 1H), 2.74 (m, 5H), 2.04-2.00 (m, 2H), 1.57-1.52 (m, 2H),1.48 (s, 9H).

Example 251: Synthesis of2-{N-Methyl-2-[methyl(piperidin-4-yl)amino]acetamido}-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamide

To a solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidedihydrochloride (55.5 mg, 0.15 mmol),2-({1-[(tert-butoxy)carbonyl]piperidin-4-yl}(methyl)amino)acetic acid(44 mg, 0.16 mmol) and N,N-diisopropylethylamine (57 mg, 0.44 mmol, 73μl) in N,N-dimethylformamide (1 ml) was added1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 61.6 mg, 0.15 mmol) and the reactionmixture stirred for 18 hours. The crude material was purified by RPHPLC(method B) to give tert-butyl4-[methyl({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl})amino]piperidine-1-carboxylateas a white foamy solid. R_(t)=4.19 min, (M+H)⁺=560.20).

tert-Butyl4-[methyl({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl})amino]piperidine-1-carboxylate was dissolved in 4N HClin 1,4-dioxane. The mixture stirred overnight and the white precipitatewas filtered on a glass frit (medium), washed with 1,4-dioxane and etherand dried under vacuum to leave2-{N-methyl-2-[methyl(piperidin-4-yl)amino]acetamido}-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamideas a white solid (61 mg, 73%). LC/MS method A: R_(t)=3.45 min.,(M+H)⁺=460. ¹H NMR (300 MHz, CD₃OD): δ 7.93-7.71 (m, 2H), 7.37 (d,J=8.80 Hz, 1H), 4.47 (m, 2H), 4.09 (m, 2H), 3.19 (s, 3H), 3.06 (m, 1H),2.37 (m, 1H), 2.02 (m, 6H), 1.33-1.16 (m, 4H).

Example 252: Synthesis of Benzyl2-{[(tert-butoxy)carbonyl](1-methylpiperidin-4-yl) amino}acetate

A mixture of benzyl 2-bromoacetate (1.3 g, 5.8 mmol),4-amino-1-methylpiperidine (2.5 g, 13 mmol) and triethylamine (0.59 g,5.8 mmol) in tetrahydrofuran (10 mL) was stirred 20 hours. Di-tert-butyldicarbonate (1 g, 4.6 mmol) was added and stirring continued for 20hours. Ethyl acetate (100 ml) was added and the mixture was washed withwater (2×50 ml), 1N HCl (50 ml), and brine (25 ml). The organic solutionwas dried over sodium sulfate and evaporated to give a crude productwhich was purified by chromatography on silica gel using a gradient ofethyl acetate in hexanes to give benzyl2-{[(tert-butoxy)carbonyl](1-methylpiperidin-4-yl)amino}acetate as acolorless oil (0.116 g, 7%). LC/MS method A: R_(t)=3.74 min.,(M+H)⁺=363. ¹H NMR (300 MHz, CDCl₃): δ 7.34 (m, 5H), 5.14 (s, 2H),4.10-3.96 (m, 1H), 3.83 (s, 1H), 2.88-2.84 (m, 2H), 2.25 (s, 3H),2.06-1.99 (m, 2H), 1.74-1.71 (m, 2H), 1.59-1.55 (m, 1H), 1.47 (s, 3H),1.36 (s, 6H).

Example 253: Synthesis of2-{[(tert-Butoxy)carbonyl](1-methylpiperidin-4-yl)amino} acetic acid

A solution of benzyl2-{[(tert-butoxy)carbonyl](1-methylpiperidin-4-yl)amino}acetate (116.2mg, 0.32 mmol) in methanol (20 mL) was hydrogenated (1 atmospherehydrogen pressure) over 10% Pd/C (100 mg) for 20 hours. The mixture wasfiltered through celite and the filtrate was evaporated to give2-{[(tert-butoxy)carbonyl](1-methylpiperidin-4-yl)amino}acetic acid as acolorless oil (89 mg, 100%). LC/MS method A: R_(t)=2.36 min.,(M+H)⁺=273.

Example 254: Synthesis ofN-Methyl-2-[(1-methylpiperidin-4-yl)amino]-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamide

To a solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidedihydrochloride (71.8 mg, 0.19 mmol),2-{[(tert-butoxy)carbonyl](1-methylpiperidin-4-yl)amino}acetic acid(56.9 mg, 0.21 mmol) and N,N-diisopropylethylamine (73.6 mg, 0.57 mmol,94 μl) in N,N-dimethylformamide (1 ml) was added1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 79.5 mg, 0.21 mmol) and the reactionmixture stirred for 18 hours. The crude material was purified by RPHPLC(method B) to give tert-butylN-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}-N-(1-methylpiperidin-4-yl)carbamatea light yellow foamy solid (138 mg). LC/MS (method A); R_(t)=4.02 min.,(M+H)⁺=560.

tert-ButylN-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}-N-(1-methylpiperidin-4-yl)carbamate was dissolved in4N HCl in 1,4-dioxane. The mixture stirred 18 hours and the whiteprecipitate was filtered on a glass frit (medium), washed with1,4-dioxane and ether and dried under vacuum to leaveN-methyl-2-[(1-methylpiperidin-4-yl)amino]-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamide as a white powder (55 mg, 51%). LC/MS method A:R_(t)=3.26 min., (M+H)⁺=460. ¹H NMR (300 MHz, CD₃OD): δ 7.72-7.94 (m,2H), 7.36 (d, J=8.80 Hz, 1H), 4.47 (m, 2H), 4.31-4.16 (m, 2H), 3.49-3.44(m, 1H), 3.19 (s, 3H), 2.89 (s, 3H), 2.46-2.41 (m, 2H), 2.06-2.02 (m,2H), 1.30-1.44 (m, 4H).

Example 255: Synthesis of tert-Butyl N-(1-acetylpiperidin-4-yl)carbamate

A mixture of tert-butyl piperidin-4-ylcarbamate (3.69 g, 18.4 mmol) andtriethylamine (5.57 g, 55 mmol) in tetrahydrofuran (10 mL) was cooled to0° C. Acetic anhydride (2.25 g, 22 mmol) was added and stirred for 18hours. Ethyl acetate (100 ml) was added and the mixture was washed withwater (2×50 ml), 1N HCl (50 ml), and brine (25 ml). The organic solutionwas dried over sodium sulfate and evaporated to give tert-butylN-(1-acetylpiperidin-4-yl)carbamate as a beige solid (4.7 g, 100%).LC/MS method A: R_(t)=3.39 min., (M+H)⁺=243. ¹H NMR (300 MHz, CDCl₃): δ4.47 (d, J=11.4 Hz, 2H), 3.77-3.75 (m, 2H), 3.15-3.06 (m, 1H), 2.80-2.66(m, 2H), 2.07 (s, 3H), 1.99-1.89 (m, 2H), 1.42 (s, 9H).

Example 256: Synthesis of N-(1-Acetylpiperidin-4-yl)amine

A solution of tert-butyl N-(1-acetylpiperidin-4-yl)carbamate (4.0 g, 17mmol) stood in 1:1 trifluoroacetic acid-methylene chloride (50 ml) for 2hours and was then evaporated to dryness to leaveN-(1-acetylpiperidin-4-yl)amine as a solid (4.4 g, 100%) which was usedwithout characterization for the next step.

Example 257: Synthesis of Benzyl2-[(1-acetylpiperidin-4-yl)amino]acetate

A mixture of benzyl 2-bromoacetate (1.3 g, 5.8 mmol),1-(4-aminopiperidin-1-yl)ethan-1-one (1.8 g, 10 mmol), and triethylamine(3 g, 30 mmol) in tetrahydrofuran (10 mL) was stirred 18 hours.Saturated sodium bicarbonate solution (50 ml) was added followed byaddition of ethyl acetate (50 ml). The organic layer was washed withwater (2×50 ml) and brine (25 ml). The organic solution was dried oversodium sulfate and evaporated to give benzyl2-[(1-acetylpiperidin-4-yl)amino]acetate as a colorless oil (1.56 g,54%). LC/MS method A: R_(t)=2.76 min., (M+H)⁺=291.

Example 258: Synthesis of Benzyl2-[(1-acetylpiperidin-4-yl)[(tert-butoxy)carbonyl]amino]acetate

A mixture of benzyl 2-[(1-acetylpiperidin-4-yl)amino]acetate (1.56 g,5.4 mmol) and triethylamine (1.09 g, 10.8 mmol) in tetrahydrofuran (10mL) was cooled to 0° C. Di-text-butyl dicarbonate (1.17 g, 5.4 mmol) wasadded and stirred for 20 hours. Ethyl acetate (100 ml) was added and themixture was washed with water (2×50 ml), 1N HCl (50 ml), and brine (25ml). The organic solution was dried over sodium sulfate and evaporatedto give a crude product which was purified by silica gel chromatographyeluted with a gradient of ethyl acetate in hexanes to leave benzyl2-[(1-acetylpiperidin-4-yl)[(tert-butoxy)carbonyl]amino]acetate as acolorless oil (0.8 g, 38%). LC/MS method A: R_(t)=4.73 min., (M+H)⁺=391.

Example 259: Synthesis of2-[(1-Acetylpiperidin-4-yl)[(tert-butoxy)carbonyl]amino] acetic acid

A solution of benzyl2-[(1-acetylpiperidin-4-yl)[(tert-butoxy)carbonyl]amino]acetate (0.8 g,2 mmol) in methanol (50 mL) was hydrogenated (1 atmosphere hydrogenpressure) over 10% Pd/C (100 mg) for 20 hours. The mixture was filteredthrough celite and the filtrate was evaporated to give2-[(1-acetylpiperidin-4-yl)[(tert-butoxy)carbonyl]amino]acetic acid asan oil (550 mg, 92%). LC/MS method A: R_(t)=3.15 min., (M+H)⁺=301.

Example 260: Synthesis of2-[(1-Acetylpiperidin-4-yl)amino]-N-methyl-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamide

To a solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidedihydrochloride (66.8 mg, 0.18 mmol),2-[(1-acetylpiperidin-4-yl)[(tert-butoxy)carbonyl]amino]acetic acid(58.4 mg, 0.19 mmol) and N,N-diisopropylethylamine (69 mg, 0.53 mmol, 88ul) in N,N-dimethylformamide (1 ml) was added1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 73.8 mg, 0.19 mmol) and the reactionmixture stirred for 18 hours. The crude material was purified by RPHPLC(method B) to give tert-butylN-(1-acetylpiperidin-4-yl)-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}carbamateas a light yellow foamy solid (LC/MS method A: R_(t)=4.74 min.,(M+H)⁺=588). tert-ButylN-(1-acetylpiperidin-4-yl)-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}carbamatewas dissolved in 4N HCl in 1,4-dioxane. The mixture stirred overnightand the white precipitate was filtered on a glass frit (medium), washedwith 1,4-dioxane and ether and dried under vacuum to leave2-[(1-acetylpiperidin-4-yl)amino]-N-methyl-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamide (68 mg, 68.5%) as a white solid. LC/MS method A: R_(t)=3.52min., (M+H)⁺=488. ¹H NMR (300 MHz, CD₃OD): δ 7.88-7.78 (m, 2H),7.38-7.35 (m, 1H), 4.68-4.65 (m, 1H), 4.44 (s, 2H), 4.27-4.12 (m, 2H),3.19 (s, 3H), 2.71-2.63 (m, 1H), 2.23-2.20 (m, 1H), 2.11 (s, 3H),1.65-1.51 (m, 2H), 1.39-1.34 (m, 4H).

Example 261: Synthesis of tert-Butyl4-{[2-(benzyloxy)-2-oxoethyl]amino}-4-methyl piperidine-1-carboxylate

A mixture of 4-methylpiperidin-4-amine (1 g, 8.76 mmol) indichloromethane (20 mL) was cooled to 0° C., Di-tert-butyl dicarbonate(1.9 g, 8.76 mmol) was added and the mixture was stirred 20 h. Thesolvent was evaporated to give a crude product to which was addedtetrahydrofuran (20 mL), followed by addition of triethylamine (3 mL, 22mmol) and benzyl 2-bromoacetate (2 g, 8.76 mmol). The mixture wasstirred 20 h. Ethyl acetate (100 ml) was added and the mixture waswashed with saturated sodium bicarbonate solution (50 ml), and brine (25ml). The organic solution was dried over sodium sulfate and evaporatedto give a crude product which was purified by RPHPLC (method B) to givetert-butyl4-{[2-(benzyloxy)-2-oxoethyl]amino}-4-methylpiperidine-1-carboxylate asa light yellowish oil (0.55 g, 17.3%). LC/MS method A: R_(t)=3.71 min.,(M+H)⁺=363.

Example 262: Synthesis of tert-Butyl4-{[2-(benzyloxy)-2-oxoethyl][(benzyloxy)carbonyl]amino}-4-methylpiperidine-1-carboxylate

To a solution of tert-butyl4-{[2-(benzyloxy)-2-oxoethyl]amino}-4-methylpiperidine-1-carboxylate(0.51 g, 1.4 mmol) in dichloromethane (5 mL) at 0° C. was added N,N-diisopropylethylamine (0.7 mL, 4.2 mmol), followed by Benzylchloroformate (0.29 g, 1.69 mmol). The reaction mixture was stirred at0° C. and naturally warmed to room temperature overnight. More N,N-diisopropylethylamine (0.7 mL, 4.2 mmol) and benzyl chloroformate(0.29 g, 1.69 mmol) was added and the reaction was stirred for 24 hours.The reaction mixture was diluted with dichloromethane (50 ml) and washedwith saturated sodium bicarbonate (50 ml) solution and brine (50 ml).The organic solution was dried over sodium sulfate and evaporated togive a crude product which was purified by RPHPLC (method B) to givetert-butyl4-{[2-(benzyloxy)-2-oxoethyl][(benzyloxy)carbonyl]amino}-4-methylpiperidine-1-carboxylate (256 mg, 37%). LC/MS method A: R_(t)=6.34 min.,(M+Na)⁺=519.

Example 263: Synthesis of2-{[(Benzyloxy)carbonyl]({1-[(tert-butoxy)carbonyl]-4-methylpiperidin-4-yl})amino}acetic acid

To a solution of tert-butyl4-{[2-(benzyloxy)-2-oxoethyl][(benzyloxy)carbonyl]amino}-4-methylpiperidine-1-carboxylate(256 mg, 0.50 mmol) in dioxane (5 mL) was added 2N LiOH (1 mL). Themixture was stirred for 20 h. 1N HCl was added slowly till the pH was 7.Extracted with ethyl acetate (100 ml) and the organic solution was driedover sodium sulfate and evaporated to give2-{[(benzyloxy)carbonyl]({1-[(tert-butoxy)carbonyl]-4-methylpiperidin-4-yl})amino}aceticacid as a colorless oil (226 mg, 100%). Used for the next step withoutfurther purification. LC/MS method A: R_(t)=5.02 min., (M+Na)⁺=429.

Example 264: Synthesis of tert-Butyl4-{[(benzyloxy)carbonyl]({[(2-ethoxy-2-oxoethyl)(methyl)carbamoyl]methyl})amino}-4-methylpiperidine-1-carboxylate

To a solution of Sarcosine ethyl ester hydrochloride (94 mg, 0.61 mmol),2-{[(benzyloxy)carbonyl]({1-[(tert-butoxy)carbonyl]-4-methylpiperidin-4-yl})amino}aceticacid (226 mg, 0.56 mmol) and N,N-diisopropylethylamine (217 mg, 1.68mmol, 300 μl) in N,N-dimethylformamide (4 ml) was added1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 233 mg, 0.61 mmol) and the reactionmixture stirred for 18 hours. The crude material was purified by RPHPLC(method B) to give tert-butyl4-{[(benzyloxy)carbonyl]({[(2-ethoxy-2-oxoethyl)(methyl)carbamoyl]methyl})amino}-4-methylpiperidine-1-carboxylate as a colorless oil (218 mg, 77%). LC/MS methodA: R_(t)=5.5 min., (M+H)⁺=506.

Example 265: Synthesis of2-(2-{[(Benzyloxy)carbonyl]({1-[(tert-butoxy)carbonyl]-4-methylpiperidin-4-yl})amino}-N-methylacetamido)aceticacid

To a solution of tert-butyl4-{[(benzyloxy)carbonyl]({[(2-ethoxy-2-oxoethyl)(methyl)carbamoyl]methyl})amino}-4-methylpiperidine-1-carboxylate (142 mg, 0.28mmol) in dioxane (1 mL) was added 2N NaOH. The mixture was stirred 20 h.1N HCl was added slowly until the pH reached 7. The product wasextracted with ethyl acetate (100 ml) and the organic solution was driedover sodium sulfate and evaporated to give a crude product which waspurified by silica gel chromatography to give2-(2-{[(benzyloxy)carbonyl]({1-[(tert-butoxy)carbonyl]-4-methylpiperidin-4-yl})amino}-N-methylacetamido)acetic acid as a colorless oil(100 mg, 75%). LC/MS method A: R_(t)=4.72 min., (M+Na)⁺=500.

Example 266: Synthesis of tert-Butyl4-{[(benzyloxy)carbonyl]({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl})amino}-4-methylpiperidine-1-carboxylate

To a solution of2-(methylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)acetamidedihydrochloride (59 mg, 0.252 mmol),2-(2-{[(benzyloxy)carbonyl]({1-[(tert-butoxy)carbonyl]-4-methylpiperidin-4-yl})amino}-N-methylacetamido)aceticacid (100 mg, 0.21 mmol) and N,N-diisopropylethylamine (81.4 mg, 0.63mmol, 104 μl) in N,N-dimethylformamide (2 ml) was added1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluoro phosphate (HATU, 95.8 mg, 0.252 mmol) and the reactionmixture stirred for 18 hours. The crude material was purified by RPHPLC(method B) to give tert-butyl4-{[(benzyloxy)carbonyl]({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl})amino}-4-methylpiperidine-1-carboxylateas a white solid (114 mg, 78%). LC/MS method A: R_(t)=6.13 min.,(M+H)⁺=694. ¹H NMR (300 MHz, CD₃OD): δ 7.84-7.77 (m, 2H), 7.35-7.27 (m,6H), 5.06 (s, 2H), 4.39 (s, 2H), 4.32-4.28 (m, 2H), 3.71-3.65 (m, 2H),3.24-3.18 (m, 2H), 3.13 (s, 3H), 2.15-2.12 (m, 2H), 1.93-1.89 (m, 2H),1.48 (s, 3H), 1.41 (s, 9H).

Example 267: Synthesis of tert-Butyl4-methyl-4-({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}amino)piperidine-1-carboxylate

A solution of tert-butyl4-{[(benzyloxy)carbonyl]({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl})amino}-4-methylpiperidine-1-carboxylate(114 mg, 2 mmol) in methanol (20 mL) was hydrogenated (1 atmospherehydrogen pressure) over 10% Pd/C (100 mg) for 20 hours. The mixture wasfiltered through celite and the filtrate was evaporated to givetert-butyl4-methyl-4-({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}amino)piperidine-1-carboxylateas a colorless oil (100 mg, 100%). LC/MS method A: R_(t)=4.22 min.,(M+H)⁺=560.

Example 268: Synthesis ofN-Methyl-2-[(4-methylpiperidin-4-yl)amino]-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamide

To a solution of tert-butyl4-methyl-4-({[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}amino)piperidine-1-carboxylate (100 mg, 0.179 mmol) in dioxane (1 mL)was added 4N HCl in 1,4-dioxane (2 mL). The mixture stirred overnightand the white precipitate was filtered, washed with 1,4-dioxane andether and dried under vacuum to leave 22 mg (22%) ofN-methyl-2-[(4-methylpiperidin-4-yl)amino]-N-({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)acetamide as a white powder. LC/MS method A: R_(t)=3.28 min.,(M+H)⁺=460. ¹H NMR (300 MHz, CD₃OD): δ 7.73-7.91 (m, 2H), 7.36 (d,J=8.50 Hz, 1H), 4.45-4.51 (m, 2H), 3.48-3.52 (m. 2H), 3.23 (s, 3H),2.07-2.38 (m, 6H), 1.45-1.64 (m, 5H).

TABLE 1 Non-limiting exemplary compounds of the disclosure. EntryStructure  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

TABLE 2 Further non-limiting exemplary compounds of the disclosure.Entry Structure  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

FORMULATIONS

The present invention also relates to compositions or formulations whichcomprise the riluzole prodrug agents according to the present invention.In general, the compositions of the present invention comprise aneffective amount of one or more riluzole prodrug agents and saltsthereof according to the present invention which are effective and oneor more excipients.

For the purposes of the present invention the term “excipient” and“carrier” are used interchangeably throughout the description of thepresent invention and said terms are defined herein as, “ingredientswhich are used in the practice of formulating a safe and effectivepharmaceutical composition.”

The formulator will understand that excipients are used primarily toserve in delivering a safe, stable, and functional pharmaceutical,serving not only as part of the overall vehicle for delivery but also asa means for achieving effective absorption by the recipient of theactive ingredient. An excipient may fill a role as simple and direct asbeing an inert filler, or an excipient as used herein may be part of apH stabilizing system or coating to insure delivery of the ingredientssafely to the stomach. The formulator can also take advantage of thefact the compounds of the

present invention have improved cellular potency, pharmacokineticproperties, as well as improved oral bioavailability. The formulationcan be used for once-a-day or multiple times per day dosage. The presentteachings also provide pharmaceutical compositions that include at leastone compound described herein and one or more pharmaceuticallyacceptable carriers, excipients, or diluents. Examples of such carriersare well known to those skilled in the art and can be prepared inaccordance with acceptable pharmaceutical procedures, such as, forexample, those described in Remington's Pharmaceutical Sciences, 17thedition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa.(1985), the entire disclosure of which is incorporated by referenceherein for all purposes. As used herein, “pharmaceutically acceptable”refers to a substance that is acceptable for use in pharmaceuticalapplications from a toxicological perspective and does not adverselyinteract with the active ingredient. Accordingly, pharmaceuticallyacceptable carriers are those that are compatible with the otheringredients in the formulation and are biologically acceptable.Supplementary active ingredients can also be incorporated into thepharmaceutical compositions. Compounds of the present teachings can beadministered orally, parenterally or as orally dissolvable tablets(“ODT's”) or sublingual preparations, neat or in combination withconventional pharmaceutical carriers. Applicable solid carriers caninclude one or more substances which can also act as flavoring agents,lubricants, solubilizers, suspending agents, fillers, glidants,compression aids, binders or tablet-disintegrating agents, orencapsulating materials. The compounds can be formulated in conventionalmanner, for example, in a manner similar to that used for known prodrugagents. Oral formulations containing a compound disclosed herein cancomprise any conventionally used oral form, including tablets, capsules,buccal forms, ODTs or other sublingual formulations, troches, lozengesand oral liquids, suspensions or solutions. In powders, the carrier canbe a finely divided solid, which is an admixture with a finely dividedcompound. In tablets, a compound disclosed herein can be mixed with acarrier having the necessary compression properties in suitableproportions and compacted in the shape and size desired. The powders andtablets can contain up to 99% of the compound.

Capsules can contain mixtures of one or more compound(s) disclosedherein with inert filler(s) and/or diluent(s) such as pharmaceuticallyacceptable starches (e.g., corn, potato or tapioca starch), sugars,artificial sweetening agents, powdered celluloses (e.g., crystalline andmicrocrystalline celluloses), flours, gelatins, gums, and the like.

Useful tablet formulations can be made by conventional compression, wetgranulation or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants, surfacemodifying agents (including surfactants), suspending or stabilizingagents, including, but not limited to, magnesium stearate, stearic acid,sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin,cellulose, methyl cellulose, microcrystalline cellulose, sodiumcarboxymethyl cellulose, carboxymethylcellulose calcium,polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodiumcitrate, complex silicates, calcium carbonate, glycine, sucrose,sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin,mannitol, sodium chloride, low melting waxes, and ion exchange resins.Surface modifying agents include nonionic and anionic surface modifyingagents. Representative examples of surface modifying agents include, butare not limited to, poloxamer 188, benzalkonium chloride, calciumstearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitanesters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate,magnesium aluminum silicate, and triethanolamine. Oral formulationsherein can utilize standard delay or time-release formulations to alterthe absorption of the compound(s). The oral formulation can also consistof administering a compound disclosed herein in water or fruit juice,containing appropriate solubilizers or emulsifiers as needed.

Liquid carriers can be used in preparing solutions, suspensions,emulsions, syrups, elixirs, and for inhaled delivery. A compound of thepresent teachings can be dissolved or suspended in a pharmaceuticallyacceptable liquid carrier such as water, an organic solvent, or amixture of both, or a pharmaceutically acceptable oils or fats. Theliquid carrier can contain other suitable pharmaceutical additives suchas solubilizers, emulsifiers, buffers, preservatives, sweeteners,flavoring agents, suspending agents, thickening agents, colors,viscosity regulators, stabilizers, and osmo-regulators. Examples ofliquid carriers for oral and parenteral administration include, but arenot limited to, water (particularly containing additives as describedherein, e.g., cellulose derivatives such as a sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols andpolyhydric alcohols, e.g., glycols) and their derivatives, and oils(e.g., fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can be an oily ester such as ethyl oleateand isopropyl myristate. Sterile liquid carriers are used in sterileliquid form compositions for parenteral administration. The liquidcarrier for pressurized compositions can be halogenated hydrocarbon orother pharmaceutically acceptable propellants.

Liquid pharmaceutical compositions, which are sterile solutions orsuspensions, can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Compositions for oral administration can bein either liquid or solid form.

Preferably the pharmaceutical composition is in unit dosage form, forexample, as tablets, capsules, powders, solutions, suspensions,emulsions, granules, or suppositories. In such form, the pharmaceuticalcomposition can be sub-divided in unit dose(s) containing appropriatequantities of the compound. The unit dosage forms can be packagedcompositions, for example, packeted powders, vials, ampoules, prefilledsyringes or sachets containing liquids. Alternatively, the unit dosageform can be a capsule or tablet itself, or it can be the appropriatenumber of any such compositions in package form. Such unit dosage formcan contain from about 1 mg/kg of compound to about 500 mg/kg ofcompound, and can be given in a single dose or in two or more doses.Such doses can be administered in any manner useful in directing thecompound(s) to the recipient's bloodstream, including orally, viaimplants, parenterally (including intravenous, intraperitoneal andsubcutaneous injections), rectally, vaginally, and transdermally.

When administered for the treatment or inhibition of a particulardisease state or disorder, it is understood that an effective dosage canvary depending upon the particular compound utilized, the mode ofadministration, and severity of the condition being treated, as well asthe various physical factors related to the individual being treated. Intherapeutic applications, a compound of the present teachings can beprovided to a patient already suffering from a disease in an amountsufficient to cure or at least partially ameliorate the symptoms of thedisease and its complications. The dosage to be used in the treatment ofa specific individual typically must be subjectively determined by theattending physician. The variables involved include the specificcondition and its state as well as the size, age and response pattern ofthe patient.

In some cases it may be desirable to administer a compound directly tothe airways of the patient, using devices such as, but not limited to,metered dose inhalers, breath-operated inhalers, multidose dry-powderinhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosoldispensers, and aerosol nebulizers. For administration by intranasal orintrabronchial inhalation,

the compounds of the present teachings can be formulated into a liquidcomposition, a solid composition, or an aerosol composition. The liquidcomposition can include, by way of illustration, one or more compoundsof the present teachings dissolved, partially dissolved, or suspended inone or more pharmaceutically acceptable solvents and can be administeredby, for example, a pump or a squeeze-actuated nebulized spray dispenser.The solvents can be, for example, isotonic saline or bacteriostaticwater. The solid composition can be, by way of illustration, a powderpreparation including one or more compounds of the present teachingsintermixed with lactose or other inert powders that are acceptable forintrabronchial use, and can be administered by, for example, an aerosoldispenser or a device that breaks or punctures a capsule encasing thesolid composition and delivers the solid composition for inhalation. Theaerosol composition can include, by way of illustration, one or morecompounds of the present teachings, propellants, surfactants, andco-solvents, and can be administered by, for example, a metered device.The propellants can be a chlorofluorocarbon (CFC), a hydrofluoroalkane(HFA), or other propellants that are physiologically and environmentallyacceptable.

Compounds described herein can be administered parenterally orintraperitoneally. Solutions or suspensions of these compounds or apharmaceutically acceptable salts, hydrates, or esters thereof can beprepared in water suitably mixed with a surfactant such ashydroxyl-propylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, and mixtures thereof in oils. Underordinary conditions of storage and use, these preparations typicallycontain a preservative to inhibit the growth of microorganisms.

The pharmaceutical forms suitable for injection can include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In some embodiments, the form can sterile and its viscositypermits it to flow through a syringe. The form preferably is stableunder the conditions of manufacture and storage and can be preservedagainst the contaminating action of microorganisms such as bacteria andfungi. The carrier can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (e.g., glycerol, propylene glycol andliquid polyethylene glycol), suitable mixtures thereof, and vegetableoils.

Compounds described herein can be administered transdermally, i.e.,administered across the surface of the body and the inner linings ofbodily passages including epithelial and mucosal tissues. Suchadministration can be carried out using the compounds of the presentteachings including pharmaceutically acceptable salts, hydrates, oresters thereof, in lotions, creams, foams, patches, suspensions,solutions, and suppositories (rectal and vaginal).

Transdermal administration can be accomplished through the use of atransdermal patch containing a compound, such as a compound disclosedherein, and a carrier that can be inert to the compound, can benon-toxic to the skin, and can allow delivery of the compound forsystemic absorption into the blood stream via the skin. The carrier cantake any number of forms such as creams and ointments, pastes, gels, andocclusive devices. The creams and ointments can be viscous liquid orsemisolid emulsions of either the oil-in-water or water-in-oil type.Pastes comprised of absorptive powders dispersed in petroleum orhydrophilic petroleum containing the compound can also be suitable. Avariety of occlusive devices can be used to release the compound intothe blood stream, such as a semi-permeable membrane covering a reservoircontaining the compound with or without a carrier, or a matrixcontaining the compound. Other occlusive devices are known in theliterature. Compounds described herein can be administered rectally orvaginally in the form of a conventional suppository. Suppositoryformulations can be made from traditional materials, including cocoabutter, with or without the addition of waxes to alter the suppository'smelting point, and glycerin. Water-soluble suppository bases, such aspolyethylene glycols of various molecular weights, can also be used.

Lipid formulations or nanocapsules can be used to introduce compounds ofthe present teachings into host cells either in vitro or in vivo. Lipidformulations and nanocapsules can be prepared by methods known in theart.

To increase the effectiveness of compounds of the present teachings, itcan be desirable to combine a compound with other agents effective inthe treatment of the target disease. For example, other active compounds(i.e., other active ingredients or agents) effective in treating thetarget disease can be administered with compounds of the presentteachings. The other agents can be administered at the same time or atdifferent times than the compounds disclosed herein.

Compounds of the present teachings can be useful for the treatment orinhibition of a pathological condition or disorder in a mammal, forexample, a human subject. The present teachings accordingly providemethods of treating or inhibiting a pathological condition or disorderby providing to a mammal a compound of the present teachings includingits pharmaceutically acceptable salt) or a pharmaceutical compositionthat includes one or more compounds of the present teachings incombination or association with pharmaceutically acceptable carriers.Compounds of the present teachings can be administered alone or incombination with other therapeutically effective compounds or therapiesfor the treatment or inhibition of the pathological condition ordisorder.

Non-limiting examples of compositions according to the present inventioninclude from about 0.001 mg to about 1000 mg of one or more riluzoleprodrug according to the present invention and one or more excipients;from about 0.01 mg to about 100 mg of one or more riluzole prodrugaccording to the present invention and one or more excipients; and fromabout 0.1 mg to about 10 mg of one or more riluzole prodrug according tothe present invention; and one or more excipients.

Procedures

The following procedures can be utilized in evaluating and selectingcompounds as riluzole prodrugs.

Stability in Simulated Gastric Fluid (SGF) and Simulated IntestinalFluid (SIF). Procedure from Baudy et. al. (J. Med. Chem. 2009, 52,771-778) used. The physiological stability of prodrugs was determined byexamining the stability of the compound in SGF, and SIF at 37° C. Thecompounds were prepared in a 9:1 mixture of the appropriate testcomponent (SGF, SIF) and acetonitrile to a final concentration of 0.01mg/mL. The samples were thoroughly mixed and maintained at 37° C. Eachsample was injected consecutively onto an Agilent 1100 system (Luna C18,3 μm, 50 mm×3 mm; 1 mL/min; mobile phase of 0.1% trifluoroacetic acid inwater/0.1% trifluoroacetic acid in acetonitrile) after a 3 h period. Thepercent remaining of prodrug was calculated by comparing the area ofprodrug compound versus riluzole generated. The identities of the parentcompounds and conversion products were confirmed by LC/MS.

Plasma Stability: Assessment of plasma stability was carried out byindividual incubations of drug candidates in fresh mouse or humancontrol plasma at a concentration of 1 uM for 1 hour at 3TC. Afterwhich, the samples were de-proteinized by addition of 2 volumes ofacetonitrile containing 0.1% formic acid and internal standard, vortexmixed for 2 minutes and centrifuged at 4000 rpm for 10 minutes to pelletprecipitated protein. The resulting supernatant containing the drugcandidates was diluted 5-fold with water containing 0.1% formic acid andsubmitted to LC-MS/MS analysis. All determinations were done intriplicate. Plasma stability was expressed as percent of controlremaining.

Metabolic Stability: In vitro metabolic stability was determined inpooled mouse or human liver microsomes (BD Gentest) at a proteinconcentration of 0.5 mg/mL in reaction buffer (100 mM KH₂PO₄, pH 7.4 and12 mM MgCl₂). Each drug candidate was added to a final concentration of1 uM. This mixture was pre-warmed to 3TC for 10 minutes prior tostarting the reaction with the addition of β-Nicotinamide adeninedinucleotide 2′-phosphate reduced (NADPH) to a final concentration of 1mM. A parallel incubation lacking NADPH served as the control. Afterincubation for 30 min at 3TC, the reactions were quenched by theaddition of acetonitrile containing 0.1% formic acid and internalstandard, vortex mixed for 2 minutes and centrifuged at 4000 rpm for 10minutes to pellet the precipitated protein. The resulting supernatantcontaining the drug candidate and its potential metabolites was diluted5-fold with water containing 0.1% formic acid and submitted to LC-MS/MSanalysis. Metabolic stability was expressed as percent of controlremaining.

LC-MS/MS Analysis: An aliquot from each incubation was analyzed byLC-MS/MS with SRM detection in the positive ionization mode using anABSciex API 5500 QTrap Mass Spectrometer interfaced via the ABSciexTurbo V IonSpray source (ESI) to an Eksigent ExpressHT LC system. Bestpeak shape and separation from interfering matrix species was affordedby an Eksigent 3C18-CL-300, 3μ, 50×1 mm column. A fast gradient, from 15to 85% organic in 2.5 minutes, with run time of 5.0 minutes, and flowrate of 50 uL/min was utilized. Peak areas were integrated usingMultiQuant v2.0 software from ABSciex.

Rat Pharmacokinetic studies of the compounds of the disclosure: Thepharmacokinetics of the compound of the disclosure and released riluzolewere evaluated following either a single intravenous or oraladministration of the prodrug to fasted male Sprague-Dawley rats atsuggested dose levels (mg/Kg body weight). Blood samples were collectedat pre-determined time points including a 0 h time point and usuallybetween 7 and 8 additional time points not exceeding a 24 h period.Plasma concentrations of the prodrug and riluzole were determined byLC-MS/MS and pharmacokinetic parameters were determined using WinNonlin(v6.3).

Plasma samples were extracted and analyzed using the methods describedin Plasma Sample Extraction and Analysis. Average plasma concentrationsfor selected examples and plasma pharmacokinetic parameters are shown inTables 2. All data are expressed as ng/mL of the free base. Samples thatwere below the limit of quantification (0.5 ng/mL) were not used in thecalculation of averages.

Pharmacokinetic parameters were calculated from the time course of theplasma concentrations. Pharmacokinetic parameters were determined withPhoenix Winnonlin (v6.3) software using a non-compartmental model. Themaximum plasma concentration (Cmax) and time to the maximum plasmaconcentration (Tmax) of the compound of the disclosure were observedfrom the data. The area under the concentration-time curve (AUC) of thecompound of the disclosure was calculated using the trapezoidal formulawith calculation to the last quantifiable data point, and to infinity ifapplicable. Plasma half-life (t1/2) was calculated from 0.693/slope ofthe terminal elimination phase. Mean residence time, MRT, was calculatedby dividing the area under the moment curve (AUMC) by the AUC. Anysamples below the limit of quantitation (0.5 ng/mL) were treated as zerofor pharmacokinetic data analysis.

Plasma Sample Extraction and Analysis: Analytical stock solutions (1.00mg/mL of the free compound of the disclosure) were prepared in DMSO.Standards were prepared in diluted matrix containing 1 part 10% formicacid and 9 parts Sprague-Dawley rat plasma containing sodium heparin asthe anticoagulant (pre-diluted with 1 part of 0.5M citric acid and 9parts whole blood). Working solutions were prepared in 50:50acetonitrile:water. Working solutions were then added to plasma to makecalibration standards to final concentrations of 1000, 500, 100, 50, 10,5, 1, and 0.5 ng/mL. Standards contained both the test article andriluzole. Standards were treated identically to the study samples.

Sample Extraction: Plasma samples were extracted via acetonitrileprecipitation on a Tomtec Quadra 96-Model 320 liquid handling system ina 96-well plate format.

Step 1

-   -   1) Standards: Add 10 μL of appropriate working solution to 50 μL        of blank matrix in a 96-well plate.    -   2) Blanks: Add 10 μL 50:50 acetonitrile:water to 50 μL of blank        matrix in a 96-well plate.    -   3) Samples: Add 10 μL 50:50 acetonitrile:water to 50 μL of study        sample in a 96-well plate.    -   4) Cap and mix.

Step 2: Using the Tomtec, add 50 μL of sample to 150 μL of acetonitrile(containing 100 ng/mL propranolol as an internal standard) that has beenpre-loaded onto a Sirocco Protein Precipitation plate (Waters Corp.)

Step 3: Using the Tomtec, mix the samples via air aspiration

Step 4: Apply vacuum and collect filtrates into clean polypropylene96-well plate. Cap for analysis.

HPLC Conditions: Instrument: Waters Acquity UPLC Column: Waters AcquityBEH C18, 100×2.1 mm id, 1.7 μm

Mobile Phase Buffer: 40 mM ammonium formate, pH 3.5Aqueous Reservoir (A): 10% buffer, 90% waterOrganic Reservoir (B): 10% buffer, 90% acetonitrile

Gradient Program:

Time Grad. (min) Curve % A % B 0.00 6 90 10 3.75 6 0 100 4.00 6 90 105.00 6 90 10

Flow Rate: 400 μL/min Injection Volume: 5 μL Run Time: 5.0 min ColumnTemperature: 40° C. Sample Temperature: 8° C.

Strong Autosampler Wash: 1:1:1 (v:v:v) water:methanol:isopropanol with0.2% formic acidWeak Autosampler Wash: 4 mM ammonium formate

Mass Spectrometer Conditions Instrument: PE Sciex API4000 Interface:Electrospray (“Turbo Ion Spray”) Mode: Multiple Reaction Monitoring(MRM) Gases: CUR 30, CAD 10, GS1 50, GS2 50 Source Temperature: 550° C.

Polarity: positive

Pharmacokinetic data for various examples via intravenous administrationis shown in Table 3. Table 4 shows pharmacokinetic data for Example 125via oral administration. FIG. 1 shows the time-concentration curves forExample 125 and released riluzole via both intravenous and oraladministration. These data demonstrate that the compounds of thedisclosure in Table 3 are converted to riluzole when givenintravenously. These data further demonstrate that the prodrug Example125 is converted to Riluzole with moderate to long half life duringintravenous administration and the prodrug Example 125 is converted toRiluzole with long half life, high oral bioavailability during oraladministration. Table 5 shows pharmacokinetic data for Example 204 viaoral administration. FIG. 3 shows the time-concentration curves forExample 204 and released riluzole via both intravenous and oraladministration. Table 6 shows pharmacokinetic data for Example 216 viaoral administration. Tables 7, 8, and 9 and FIGS. 5 and 6 show PK datafor example 204 in mice and cynomolgus monkey

TABLE 3 PK in fasted male Sprague Dawley Rats, IV administration.Monitor disappearance of Prodrug and appearance of riluzole.^(a)Compound of the disclosure values released riluzole values Cl AUC_(last)V_(ss) C_(max) AUC_(last) Example (L/h/Kg) t_(1/2) (h) (hr · ng/mL)(L/Kg) t_(1/2) (h) T_(max) (h) (ng/mL) (hr · ng/mL) 52 0.54 4.75 36233.55 ND 6.67 42.4 280 59 0.64 6.2 2766 5.11 ND 8 39.9 222 82 4.28 1.03663 4.14 3.07 2 198 1121 83 0.68 5.56 1725 5.06 ND 5.33 24.8 171 1110.345 6.51 4647 3.19 ND 5.33 24.6 153 113 0.69 5.45 2758 4.88 ND 6.67 92530 118 1.13 10.4 2484 3.35 16.8 0.083 49.5 165 119 1.63 9.3 1721 4.7 ND2.92 16.9 118 120 1.14 8.66 2465 3.63 76.7 0.083 30.7 132 121 2.18 4.831294 6.15 ND 1.39 49.6 286 122 3.98 0.28 219 0.861 4.01 0.08 560 2017123 3.54 0.68 787 2.04 4.13 0.14 375 1655 124 4.87 0.63 580 2.67 2.991.33 324 1577 125 1.78 1.93 1526 3.57 7.83 0.78 187 1137 125 1.67 1.921602 3.51 4.71 0.19 324 1452 173 1.34 6.7 1444 9.66 ND 8 26 159 204 13.20.237 232 2.47 3.77 0.53 392 1300 212 6.26 2.43 218 6.21 4.64 0.083 315208 216 1.38 3.98 1907 2.53 9.05 0.42 156 830 234 0.853 1.5 3245 1.105.39 0.78 18.3 73.3

IV administration of prodrug at dose of 2.8 mg/Kg except example 83which was 1.8 mg/Kg and Example 212 which was dosed at 1.4 mg/Kg

ND=not determined

CL=Clearance

t_(1/2)=Terminal Half LifeV_(SS)=Volume of distributionTmax=Time at maximum concentrationCmax=Maximum concentration

TABLE 4 PK in fasted male Sprague Dawley Rats for Example 125, POadministration at 14 mg/kg. Monitor disappearance of Prodrug andappearance of riluzole. Example 125 Released Riluzole Mean SD Mean SDC_(max) 213 39.0 C_(max) 1587 150 (ng/mL) (ng/mL) t_(max) (hr) 1.80 2.00t_(max) (hr) 8.00 0 t_(1/2) (hr) 3.8 0.40 t_(1/2) (hr) ND ND AUC_(last)2259 305 AUC_(last) (hr · ng/mL) (hr · ng/mL) 20518 1437 AUC_(inf) 228932 AUC_(inf) ND ND (hr · ng/mL) (hr · ng/mL) % F 26 % F >100 % F =bioavailability

TABLE 5 PK in fasted male Sprague Dawley Rats for Example 204, POadministration at 5 mg/kg. Monitor disappearance of Prodrug andappearance of riluzole. Example 204 Riluzole Mean SD Mean SD C_(max)1.84 0.27 C_(max) 442 104.0 (ng/mL) (ng/mL) t_(max) (hr) 0.28 0.21t_(max) (hr) 5.33 2.31 t_(1/2) (hr) ND ND t_(1/2) (hr) ND ND AUG_(last)0.90 ND AUG_(last) 2332 791 (hr · ng/mL) (hr · ng/mL)

TABLE 6 PK in fasted male Sprague Dawley Rats for Example 216, POadministration at 5 mg/kg. Monitor disappearance of Prodrug andappearance of riluzole. Example 216 Riluzole Mean SD Mean SD C_(max)2.96 0.56 C_(max) 81.8 43 (ng/mL) (ng/mL) t_(max) (hr) 2.17 1.76 t_(max)(hr) 5.33 2.31 t_(1/2) (hr) ND ND t_(1/2) (hr) ND ND AUG_(last) 16.61.77 AUG_(last) 426 226 (hr · ng/mL) (hr · ng/mL)

TABLE 7 PK in fasted male mice for Example 204, IV administration, 1mg/kg. Monitor disappearance of Prodrug and appearance of riluzole.Example 204 Riluzole Mean SD Mean SD T_(1/2) (hr) 0.29 0.06C_(max)(ng/mL) 45 13 CL (L/hr/kg) 1.94 0.44 T_(max)(hr) 083 0 Vss (L/kg)0.46 0.14 T_(1/2) (hr) 2.3 0.20 AUC_(last) 532.0 109.0 AUC_(last) 118 6(hr.ng/mL) (hr.ng/mL) AUC_(inf) 533 109.0 AUC_(inf) 130 5 (hr.ng/mL)(hr.ng/mL)

TABLE 8 PK in fasted male mice for Example 204, PO administration, 5mg/kg. Monitor disappearance of Prodrug and appearance of riluzole.Example 204 Riluzole Mean SD Mean SD C_(max)(ng/mL) 4.71 1.52C_(max)(ng/mL) 79 26.1 Tmax(hr) 0.33 0.14 Tmax(hr) 2.0 0.0 T_(1/2) (hr)ND ND T_(1/2) (hr) ND ND AUC_(last) 3.85 2.36 AUClast 332 52 (hr.ng/mL)(hr.ng/mL) AUC_(inf) ND ND AUC_(inf) ND ND (hr.ng/mL) (hr.ng/mL)

TABLE 9 PK in Cynomolgus Monkey for Example 204, IV administration 1mg/kg and PO administration, 3 mg/kg. Monitor the appearance ofriluzole. Riluzole from Riluzole from example 204 example 204 (IV, 1mg/kg) (PO, 3 mg/kg) Mean SD Mean SD C_(max) 60 5.7 C_(max) 200 89.2(ng/mL) (ng/mL) t_(max) (hr) 0.75 0.3 t_(max) (hr) 2.33 0.82 t_(1/2)(hr) 6.2 1.3 t_(1/2) (hr) 5.9 2.11 AUC_(last) 293 97.9 AUC_(last) 2110920 (hr · ng/mL) (hr · ng/mL)

Inhibition of Human Melanoma Cell Xenograft Growth by Riluzole: MelanomaC8161 cells were inoculated s.c. into nude mice at 10 per site. The micewere treated with 7.5 mg/kg riluzole (control), an equimolar amount ofprodrug (Example 125, 14.6 mg/kg), and a dose of prodrug Example 125threefold lower in molar terms (4.9 mg/kg) than the dose of riluzole, byp.o. gavage when tumor volume had reached 6 mm³. Mice were treated everyday for 21 days, and tumor sizes were measured twice weekly with aVernier caliper. The results are shown in FIG. 2. These data demonstratea significant reduction in tumor volume in mice treated with riluzoleand both doses of prodrug Example 125 compared with untreated orvehicle-treated controls. Bars represent SD; *, P<0.01, compared withuntreated and DMSO

treated (t test). An additional study was conducted using example 204using doses of 5.0 mg/kg, 1.7 mg/kg, and 0.56 mg/kg. The results of thestudies using example 204 are shown in FIG. 4.

Clinical Study of BHV-4157 (Example 204) for Treating Patients withAlzheimer's Disease Study Example 1

A clinical study is conducted with the following parameters. Foradditional information, refer to ClinicalTrials.gov IdentifierNCT03605667, www.clinicaltrials.gov.

Study Description Brief Summary

Preclinical models suggest that riluzole, the active metabolite ofBHV-4157, may protect from AD-related pathology and cognitivedysfunction. Titrated dose of BHV-4157 to 280 mg, or placebo, takenorally once daily. Duration of treatment is 48 weeks. There is also ascreening period of up to 42 days; and a 4-week post-treatmentobservation period.

Condition or disease Intervention/treatment Phase Alzheimer DiseaseDrug: troriluzoleDrug: Phase 2/ Placebo oral capsule Phase 3

Study Design

Study Type: Interventional (Clinical Trial) Estimated Enrollment: 292participants Allocation: Randomized Intervention Model: ParallelAssignment Masking: None (Open Label) Primary Purpose: TreatmentOfficial Title: A Phase 2 Randomized Double- Blind Placebo-ControlledTrial to Evaluate the Efficacy and Safety of BHV-4157 in Patients WithMild to Moderate Alzheimer's Disease

Arms and Interventions

Arm Intervention/treatment Experimental: BHV-4157 Drug: troriluzoletroriluzole, Oral BHV-4157 will be given 280 mg capsules, UD daily forup to 48 weeks Other Name: BHV-4157 Placebo Comparator: Drug: PlaceboPlacebo matching 280 mg oral capsule placebo capsules, QD Oral matchingplacebo will be given daily for up to 48 weeks

Outcome Measures Primary Outcome Measures:

-   -   1. The change in Alzheimer's Disease Assessment Scale Cognitive        Subscale (ADAS-Cog 11) from baseline to week 48 between the        BHV-4157 treatment group and the placebo group [Time Frame:        Baseline to Week 48]

Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog 11)

The ADAS-Cog 11 evaluates memory (word recall, word recognition),reasoning (following commands), language (naming, comprehension),orientation, ideational praxis (placing a letter in an envelope) andconstructional praxis (copying geometric designs). Ratings of spokenlanguage, language comprehension, word finding difficulty, and abilityto remember test instructions are also obtained. The test is scored interms of errors, with higher scores reflecting poorer performance andgreater impairment. Scores can range from 0 (best) to 70 (worse).

Eligibility Criteria

50 Years to 85 Years Ages Eligible for Study: (Adult, Older Adult) SexesEligible for Study: All Accepts Healthy Volunteers: No

Criteria

Key Inclusion Criteria:

-   -   Age 50 to 85 (inclusive) at screening    -   Diagnosed with probable Alzheimer's disease dementia: Core        clinical criteria in accordance with NIA/Alzheimer's Association        Guidelines.    -   Living in the community (includes assisted living facilities,        but excludes long-term care nursing facilities).    -   Ambulatory, or able to walk with an assistive device, such as a        cane or walker.    -   Participants must have a study partner who has frequent        interaction with them (approximately >3-4 times per week), will        be present for all clinic visits, and can assist in compliance        with study procedures.    -   A brain MRI scan within 6 months of screening consistent with a        diagnosis of Alzheimer's disease.    -   Participants should be treated with a stable dosage regimen of        FDA-approved AD medications (acetylcholinesterase inhibitors        (AchEI) and/or memantine) for at least 3 months prior to        screening. Participants should be expected to remain on a stable        dosage regimen of these medications for the duration of the        trial.    -   Participants who are not being treated with FDA-approved AD        medications at the time of screening, because they have        contraindications to these medications, or because they have        previously failed treatment with these medications, are also        eligible for inclusion, if it is expected that they will not be        treated with these medications for the duration of the trial.

Key Exclusion Criteria:

-   -   Hepatic impairment defined as Child-Pugh class of A or more        severe liver impairment.    -   Other neurodegenerative diseases and causes of dementias,        including Parkinson's disease and Huntington's disease, vascular        dementia, CJD (Creutzfeldt-Jakob disease), LBD (Lewy Body        dementia), PSP (Progressive Supranuclear Palsy), AIDS (Acquired        Immunodeficiency Syndrome), or NPH (normal pressure        hydrocephalus).    -   History of a major depressive episode within the past 6 months        of screening.    -   Insulin-dependent diabetes or uncontrolled diabetes with HbA1c        value >8.0%.    -   Cancer or a malignant tumor within the past 3 years, except        patients who underwent potentially curative therapy with no        evidence of recurrence for >3 years. Patients with stable        prostate cancer or non-melanoma skin cancers are not excluded.    -   Participation in another clinical trial for an investigational        agent and having taken at least one dose of study medication,        unless confirmed as having been on placebo, within 12 weeks        prior to screening. The end of a previous investigational trial        is defined as the date of the last dose of an investigational        agent.

Study Example 2

A clinical study is conducted with the following parameters.

Study Summary

Title A Phase 2 Randomized Double-Blind Placebo-Controlled Trial toEvaluate the Efficacy and Safety of BHV-4157 in Patients with Mild toModerate Alzheimer's Disease Rationale BHV-4157 is a new chemical entity3rd-generation prodrug of the glutamate modulator, riluzole, which hasbeen designed to bypass first- pass metabolism therein providing greaterbioavailability, diminished PK variability, lower hepatic burden, lackof food effect, longer half-life and once daily dosing. Preclinicalmodels suggest that riluzole, the active metabolite of BHV-4157, mayprotect from AD-related pathology and cognitive dysfunction. Target Maleand females, age 50 to 85 years (inclusive at screening), diagnosedPopulation with Alzheimer's Disease (in accordance with NIA/Alzheimer'sAssociation Guidelines) of mild to moderate severity including MMSEscore 14-24 at the screening visit. Eligible participants should bereceiving a stable dose of FDA-approved AD medication(s)(acetylcholinesterase inhibitors (AchEl) and/or memantine) for at least3 months prior to screening and willing to remain on same dose(s) fortrial duration. Those participants with contraindications or failedtreatment with either AchEl and/or memantine will be eligible forinclusion. Number of Approximately 292 participants will be randomlyallocated using a 1:1 Participants allocation to active treatment orplacebo. Drug Titrated dose of BHV-4157 to 280 mg, or placebo, takenorally once daily. Dosage & Duration of treatment is 48 weeks. There isalso a screening period of up Treatment to 42 days; and a 4-weekpost-treatment observation period. Duration The primary objective is to:evaluate the efficacy of BHV-4157 as Objectives measured by the ADAS-Cog11. The key secondary objective is to: evaluate the efficacy of BHV-4157as measured by the CDR-Sum of Boxes. The secondary objectives are to:(1) evaluate the efficacy of BHV-4157 as measured by: Quarc volumetricMRI (bilateral hippocampal volume, bilateral lateral ventricles, andwhole brain volume), Neuropsychiatric Inventory (NPI), ADCS-ADL,neuropsychological test battery (Craft Story 21 Recall (Immediate &Delayed), Benson Figure (Copy & Delayed Recall), Multilingual NamingTest (MINT), Letter & Category Fluency, Trail Making Test A & B, NumberSpan Forward & Backward), Mini-Mental State Examination (MMSE), andMontreal Cognitive Assessment (MoCA); (2) evaluate the safety andtolerability of BHV-4157 as measured by mortality rates, serious adverseevents, adverse events, clinical safety laboratories, physicalexaminations and significant ECG changes. Exploratory objectives are to:(1) assess pharmacokinetics of BHV-4157 (2) assess treatment response inparticipants with typical vs. atypical Alzheimer's disease presentationas well as by Apo E genotype; (3) evaluate a panel of CSF, serum andplasma biomarkers (AR42, AR42/40 ratio, total tau, p-tau, neurogranin,NfL, YKL-40, VILIP, SNAP-25, sTREM2) in a subset of the study population(estimated n =50 active, n =50 placebo) at screening, week 24 and week48. Study This is a phase 2 multi-center, randomized, double blind,placebo- Design & controlled, parallel group study. MMSE score (14 to19; 20 to 24) at Statistical screening and Site will be stratificationfactors. Plan An Interim Futility Analysis for proof-of-concept will beconducted when a sentinel cohort consisting of the first 50 randomizedparticipants in each arm has received 24 weeks of treatment or longer onstudy (completers only analysis). At this point, an interim data freeze(database snapshot) will take place and the analyses will be conductedusing the frozen data set. The study will continue if any one of thefollowing conditions is met, using a one-sided test at the statedsignificance level: Mean change from baseline to interim analysis onADAS-Cog 11: Treatment-Control is significantly improved at the p ≤ 0.50level. Mean change from screening to interim analysis on MRI Quarchippocampal volume: Treatmen-Control is significantly improved at the p≤ 0.20 level. If both conditions fail, the DSMB will indicate thatfutility criteria have been met to the Study Steering Committee (SSC)who are overseeing the trial. The SSC will have the final responsibilityfor the decision to stop the trial. This interim analysis is designed tostop with a probability of 40% under the assumption that the twoendpoints are independent and that there is no true difference betweenarms in both of the interim measures above. Overall study power at thefinal analysis: Given that the interim analysis has power of 86%, andthat the interim and final endpoints have correlation of at least 20%,the overall study has 80% power to detect a difference of 2.5 points onthe ADAS-Cog 11 at week 48 (SD 6 points), at two-sided 5% significancelevel. At the final analysis, there is also 80% power to detect a meanincrease of 0.9 points on CDR-SOB (key secondary endpoint) at 48 weeks,which corresponds to a decline in the active arm of about 40% or less ofthe placebo arm decline. The primary and key secondary endpoints at thefinal analysis will be tested using a hierarchical gatekeeper strategy:if ADAS-Cog 11 is significant at the 5% level, then CDR-SOB will also betested at 5% significance level. If both primary and key secondaryoutcomes are significant, the remainder of the secondary outcomes willbe tested at overall 5% significance level using a Holm's step downtest. This will preserve alpha at 5% overall for all endpoints tested.Statistical methods: Both the interim and final analysis will use amixed effects repeated measures model. Primary The change in ADAS-Cog 11from baseline to week 48 between the BHV- Endpoint 4157 treatment groupand the placebo group. Secondary The change in CDR-Sum of Boxes frombaseline to week 48 between the Endpoints BHV-4157 treatment group andthe placebo group. The change in MRI Quarc bilateral hippocampal volume,bilateral lateral ventricles, and whole brain volume from screening toweek 48. The change in the NPI total score from baseline to weeks 24 and48. The change in ADCS-ADL from baseline to weeks 24 and 48. The changein composite score from baseline to week 48 on the neuropsychologicaltest battery (Craft Story 21 Recall (Immediate & Delayed), Benson Figure(Copy & Delayed Recall), Multilingual Naming Test (MINT), Letter &Category Fluency, Trail Making Test A & B, Number Span Forward &Backward). The change in MMSE from baseline to weeks 24 and 48. Thechange in MoCA scores from baseline to weeks 24 and 48. The change insafety and tolerability measures including: (1) adverse events; (2)clinical laboratory tests; (3) vital signs; (4) physical examinations;(5) ECGs.

List of Abbreviations Aβ β-Amyloid AchEI Acetylcholinesterase InhibitorAD Alzheimer's Disease

ADAS-Cog Alzheimer's Disease Assessment Scale-Cognitive (subscale)

ADCS-ADL Alzheimer's Disease Cooperative Study—Activities of DailyLiving ADME Absorption, Distribution, Metabolism, Excretion AICDAutomatic Implanted Cardioverter Defibrillator AUC Area Under the CurveAE Adverse Event AIDS Acquired Immunodeficiency Syndrome ALS AmyotrophicLateral Sclerosis ALT Alanine Aminotransferase ApoE Apolipoprotein E ASTAspartate Aminotransferase BDNF Brain-derived Neurotrophic Factor BIDTwice per day BUN Blood Urea Nitrogen CDR-SOB Clinical DementiaRating—Sum of Boxes CFR Code of Federal Regulations CJDCreutzfeldt-Jakob Disease CONSORT Consolidated Standards of ReportingTrials CPK Creatinine Phosphokinase CSF Cerebrospinal Fluid CYPCytochrome P450 DMP Data Management Plan DSM Diagnostic and StatisticalManual of Mental Disorders DSMB Data Safety & Monitoring Board

eCRF Electronic Case Report Form

ECG Electrocardiogram EDC Electronic Data Capture FDA Food & DrugAdministration GCP Good Clinical Practice GGT Gamma-Glutamyl TransferaseGMP Good Manufacturing Practice HCV Hepatitis C Virus HDL High-DensityLipoprotein HIPAA Health Insurance Portability & Accountability Act

hr (unit) Hour

ICF Informed Consent Form ICH International Conference on HarmonizationIRB Institutional Review Board ITT Intent-To-Treat

kg (unit) Kilogram

LAR Legally Authorized Representative LBD Lewy Bodies Dementia LDHLactate Dehydrogenase LDL Low-Density Lipoprotein LFT Liver FunctionTest LP Lumbar Puncture MAD Multiple Ascending Dose MCI MultipleCerebral Infarctions MINT Multi-lingual Naming Test

mITT Modified Intent-To-Treatmg (unit) Milligramml (unit) Milliliter

MMSE Mini-Mental State Examination MoCA Montreal Cognitive AssessmentMRI Magnetic Resonance Imaging NfL Neurofilament Light (Protein)

ng (unit) Nanogram

NIA National Institute on Aging

NOAEL No-observed-adverse-effect-level

NPH Normal Pressure Hydrocephalus NPI Neuropsychiatric Inventory OHRPOffice of Human Research Protection PHI Personal Health Information PIPrincipal Investigator PK Pharmacokinetic PP Per Protocol PSPProgressive Supranuclear Palsy QD Once per day Quarc QuantitativeAnatomical Regional Change RBC Red Blood Cell SAD Single Ascending DoseSAE Serious Adverse Event SAP Statistical Analysis Plan SCASpinocerebellar Ataxia SD Standard Deviation SSC Study SteeringCommittee

sTREM2 Soluble Variant Triggering Receptor Expressed on Myeloid Cells 2

ULN Upper Limit of Normal USPI United States Prescribing InformationVILIP Visinin-Like Protein

vMRI Volumetric Magnetic Resonance Imaging

WBC White Blood Cell 1 Study Design

This is a phase 2 multi-center, randomized, double blind,placebo-controlled, parallel group study in patients with mild tomoderate Alzheimer's disease.

Participants will be randomized to one of two groups: 280 mg of BHV-4157or placebo. The BHV-4157 treatment dose of 280 mg was selected forevaluation in the current study based on evidence summarized in Section1.8. Treatment duration is 48 weeks (12 months). There is a screeningperiod of up to 42 days and a 4-week post-treatment observation period.

An interim analysis for futility will be conducted when a sentinelcohort consisting of the first 50 randomized participants in each armhas received 24 weeks of treatment or longer on study (completers onlyanalysis). The interim analysis is based on the change, from baseline toweek 24, of two measures, including: the surrogate primary endpoint(ADAS-Cog 11) and hippocampal volume change.

2 Objectives 2.1 Primary Objective

The primary objective is to evaluate the efficacy of BHV-4157 asmeasured by ADAS-Cog 11.

2.2 Secondary Objectives

The secondary objectives are to evaluate the efficacy, safety andtolerability of BHV-4157 as outlined below.

2.2.1 Efficacy

The efficacy of BHV-4157 will be assessed by the following measures:

-   -   CDR-Sum of Boxes (key secondary objective),    -   Volumetric MRI (Quarc bilateral hippocampal volume, bilateral        lateral ventricles, and whole brain volume),    -   Neuropsychiatric Inventory (NPI),    -   Alzheimer's Disease Cooperative Study (ADCS)-Activities of Daily        Living (ADCS-ADL),    -   Neuropsychological test battery (Craft Story 21 Recall        (Immediate & Delayed), Benson Complex Figure (Copy & Delayed        Recall), Multi-lingual Naming Test (MINT), Letter & Category        Fluency, Trail Making Test A & B, Number Span Forward and        Backward),    -   Mini-Mental State Examination (MMSE), and    -   Montreal Cognitive Assessment (MoCA).

2.2.2 Safety and Tolerability

The safety and tolerability of BHV-4157 will be assessed by thefollowing measures:

-   -   Mortality rates,    -   Serious adverse event rates,    -   Adverse events,    -   Clinical safety laboratories,    -   Vital signs,    -   Physical examinations,    -   ECGs, and    -   Use of concomitant medications.

3 Endpoints 3.1 Primary Endpoint

The primary efficacy endpoint is the within-participant change inADAS-Cog 11 from baseline to week 48, compared between the treatmentgroup and the placebo group.

3.2 Secondary Endpoints

The secondary endpoints will measure the efficacy, and safety andtolerability of BHV-4157 as outlined below.

3.2.1 Efficacy

The efficacy of BHV-4157 will be assessed by the within-participantchanges from baseline to week 48, compared between the treatment groupand the placebo group, on the following:

-   -   CDR-Sum of Boxes (key secondary endpoint),    -   Volumetric MRI (Quarc bilateral hippocampal volume, bilateral        lateral ventricles, and whole brain volume)    -   Neuropsychiatric Inventory (NPI) scores    -   Alzheimer's Disease Cooperative Study (ADCS)-Activities of Daily        Living (ADCS-ADL) scores    -   Neuropsychological test battery scores (Craft Story 21 Recall        (Immediate & Delayed), Benson Complex Figure (Copy & Delayed        Recall), Multi-lingual Naming Test (MINT), Letter & Category        Fluency, Trail Making Test A & B, Number Span Forward and        Backward),    -   Mini-Mental State Examination (MMSE) scores, and    -   Montreal Cognitive Assessment (MoCA) scores.

3.2.2 Safety and Tolerability

The following safety and tolerability measures will be assessed fordifferences between the treatment group and the placebo group:

-   -   Occurrence of mortality events,    -   Occurrence of serious adverse events (SAEs),    -   Occurrence of adverse events (AEs),    -   Clinical laboratory tests,    -   Vital signs,    -   Physical examinations,    -   ECGs, and    -   Use of concomitant medications.

4 Study Drug 4.1 Study Medication

The study medication will be presented as one of the following:

-   -   BHV-4157, 1 or 2 capsules (size 1) of 140 mg each, depending on        assigned dose    -   1 or 2 capsules of matching Placebo

The study medication capsule should not be opened.

The study medication will be securely stored at the study site inaccordance with the conditions specified on the label, separately fromother drugs. The study medication may not be used for any purpose otherthan this study.

4.2 Blinding

This is a double-blind placebo-controlled trial. Treatments will beblinded to the participants and study personnel throughout the study.Treatment blind will be maintained by use of matching placebomedication.

Only in the case of an emergency, when knowledge of whether theparticipant has received the investigational product is essential forthe clinical management or welfare of the participant, may theInvestigator unblind a participant's treatment assignment. Proceduresfor emergency unblinding are initiated by contacting the ADCS MedicalMonitor.

5 Patient Selection 5.1 Inclusion Criteria

Participants must meet all of the following inclusion criteria to beeligible for enrollment:

-   -   1. Age 50 to 85 (inclusive) at screening    -   2. Diagnosed with probable Alzheimer's disease dementia: Core        clinical criteria in accordance with NIA/Alzheimer's Association        Guidelines.    -   3. Living in the community (includes assisted living facilities,        but excludes long-term care nursing facilities).    -   4. Ambulatory, or able to walk with an assistive device, such as        a cane or walker.    -   5. Participants must have a study partner who has frequent        interaction with them (approximately >3-4 times per week), will        be present for all clinic visits, and can assist in compliance        with study procedures.    -   6. Female patients must be post-menopausal for at least 2        consecutive years or surgically sterile (bilateral tubal        ligation, hysterectomy or bilateral oophorectomy) for at least 6        months prior to screening.    -   7. A modified Hachinski score of 4 or less at screening.    -   8. An MMSE score of 14 to 24, inclusive, at screening.    -   9. A brain MRI scan within 6 months of screening consistent with        a diagnosis of Alzheimer's disease.    -   10. Body mass index (BMI) 35 kg/m² at screening.    -   11. Participants should be treated with a stable dosage regimen        of FDA-approved AD medications (acetylcholinesterase inhibitors        (AchEI) and/or memantine) for at least 3 months prior to        screening. Participants should be expected to remain on a stable        dosage regimen of these medications for the duration of the        trial.        -   a. Participants who are not being treated with FDA-approved            AD medications at the time of screening, because they have            contraindications to these medications, or because they have            previously failed treatment with these medications, are also            eligible for inclusion, if it is expected that they will not            be treated with these medications for the duration of the            trial.    -   12. Ability (patients and their study partners) to read, speak        and understand English or Spanish to ensure compliance with        cognitive testing and study visit procedures.    -   13. Provision of informed consent from the participant (or the        participant's legally authorized representative (LAR) if unable        to provide consent) and the study partner.        5.2 vMRI Assessments

Brain structural change is seen in normal aging, but is accelerated inneurodegenerative disease, including AD. Atrophy in AD arises fromneuron and synapse loss that begins in the entorhinal cortex. Thepathology then spreads throughout the limbic regions of the temporallobe, including the hippocampal formation. Subsequently, neuron loss andatrophy is observed throughout neocortical association areas intemporal, parietal and frontal lobes.

vMRI allows the in vivo assessment of brain structure volume andprovides a measure of atrophy rate. Results from vMRI studies suggestthat the patterns of atrophy in AD, which mirror the pathologicalprogression of the disease, can reliably be detected and tracked acrosstime. Atrophy of the medial temporal lobe, including hippocampus andentorhinal cortex, has long been described in vMRI studies of AD.Hippocam pal volume derived from MRI correlates with histologicalhippocampal volume and degree of neuronal loss and AD pathology, andentorhinal cortical thickness change appears to be an early andsensitive indicator of neurodegeneration associated with AD (Holland etal., 2009; Jack et al., 2004). Longitudinal MRI measures of regional andwhole-brain volumetric change provide a valuable complement to cognitivemeasures in that they are not influenced by temporary symptomaticimprovements, and they provide an early index of the study drug'sability to reach the target organ and have an effect on AD-relatedatrophy.

Participants will undergo vMRI scans of the brain at screening, week 24and week 48 in order to assess for changes in brain volumes that may beassociated with clinical change due to treatment with BHV-4157.

Volumetric MRI scans will use the same imaging protocol, which willinclude a localizer scan, a 3D T1-weighted sagittal acquisition (MPRAGEor IR-SPGR), a T2-weighted FLAIR axial acquisition, a T2* gradientrecalled echo axial acquisition for magnetic susceptibility, and adiffusion weighted axial acquisition to assess for restricted diffusion.

Images will be checked for image quality and adherence to scanningprotocols. 3D T1-weighted datasets passing quality checks will becorrected for spatial distortion and for intensity variation. Screeningand follow-up datasets for each participant will be spatially registeredto one another using rigid-body registration followed by nonlinearregistration and neuroanatomic parcellation to quantify whole-brain andsubregional volumetric change on a patient-by patient basis.

The local MRI results will determine eligibility for each participant inthe trial. It is It is the responsibility of the PI to make thisdetermination following review of the MRI, and to sign as well as datethe local report to acknowledge their review, and to confirm that theMRI results are consistent with AD and do not meet exclusion criteria.The PI is at liberty to consult with a local neuroradiologist, howeverthere is no requirement for a formal MRI read from a neuroradiologist.The ADCS Medical Safety team, or ADCS Imaging core are available toaddress any questions surrounding MRI eligibility. If there are safetyconcerns are identified on this MRI, the PI should communicate with theparticipant's Primary Care Physician and consult with ADCS MedicalMonitor, ADCS Director, and ADCS Imaging Core.

Whole brain volume (WBV, excluding cerebellum), bilateral ventricularvolume and bilateral hippocampal volume will be measured. Quantitativeanatomical regional change (Quarc) will be used as the computational MRimage processing application. Detail for the statistical computations isgiven in the Statistical Analytical Plan (SAP).

If performed on the same day as a lumbar puncture, the vMRI should beconducted before the lumbar puncture. Otherwise, at least a 3-day windowbetween vMRI and the lumbar puncture is required. Scanners that havepassed the study's qualification procedures will be used. Participantsmust be scanned by the same scanner throughout the study.

Participants with a contraindication to MRI at the time of screening aredeemed ineligible to participate in this study. Participants maycontinue to participate on the study if they have already beenrandomized but develop a contraindication to MRI during the course ofthe study.

5.3 CSF, Serum and Plasma Substudy Assessments

CSF, serum and plasma will be taken at screening within 14 days prior tofirst dose of study drug and within 14 days prior to weeks 24 and 48 tomeasure biomarkers (Aß42, Aß42/40 ratio, total tau, p-tau, neurogranin,NfL, YKL-40, VILIP, SNAP-25, sTREM2).

CSF samples should be collected at the same time of day, either morning(between 8 and 10 AM) or afternoon (between 1 and 3 PM). The firstlumbar puncture must be conducted prior to initiation of study drug.Plasma samples for PK should be drawn at the time of lumbar puncture.Date and time of doses on the day of lumbar puncture and day priorshould be collected in case report forms, for entry into the EDC system.

The estimated 100 participants (n=50 active, n=50 placebo) who arewithin the sentinel cohort that constitute the study sample for thefutility analysis will also have the opportunity to participate in aCSF, serum, and plasma substudy, with samples drawn in the screeningperiod and at week 24, with the option for a third sampling timepoint atweek 48.

In addition to the sentinel substudy participants, other consentingtrial participants will be approached to undergo a blood draw to provideserum and plasma biomarkers. For CSF, consenting participants willundergo a lumbar puncture at screening within 14 days prior to firstdose of study drug and within 14 days prior to week 48 to measure theCSF biomarkers. Anti-platelet and anticoagulant medications and lumbarpuncture are addressed above in in (Prohibited Concomitant Medications.Participants who are taking anticoagulants or dual antiplatelet drugsare excluded from the CSF substudy.

Details of the CSF sampling are contained in the Study ProceduresManual.

The unused portion of CSF may be transferred to the National CellRepository for Alzheimer's Disease (NCRAD) for future research.Participants will be given the choice to allow such sample retention andfurther investigation of their CSF.

6 Study-Specific Instruments 6.1 Cognitive Measures 6.1.1 Alzheimer'sDisease Assessment Scale Cognitive Subscale (ADAS-Cog 11)

The ADAS-Cog 11 (Rosen, Mohs, & Davis, 1984) is a structured scale thatevaluates memory (word recall, word recognition), reasoning (followingcommands), language (naming, comprehension), orientation, ideationalpraxis (placing a letter in an envelope) and constructional praxis(copying geometric designs). Ratings of spoken language, languagecomprehension, word finding difficulty, and ability to remember testinstructions are also obtained. The test is scored in terms of errors,with higher scores reflecting poorer performance and greater impairment.Scores can range from 0 (best) to 70 (worse).

6.1.2 Mini-Mental State Examination (MMSE)

The MMSE is a frequently used screening instrument for Alzheimer'sdisease drug trials. It evaluates orientation, memory, attention,concentration, naming, repetition, comprehension, and ability to createa sentence and to copy two intersecting pentagons (Folstein, Folstein, &McHugh, 1975). A lower score indicates more cognitive impairment. Thehighest (best) score is 30.

6.1.3 Montreal Cognitive Assessment (MoCA)

The MoCA is a brief mental status exam which was designed to be moresensitive to mild cognitive impairment and early dementia than the MMSE(Nasreddine et al., 2005). It assesses numerous cognitive domains,including attention and concentration, executive functions, memory,language, visuoconstructional skills, conceptual thinking, calculations,and orientation. Like the MMSE, the highest (best) score is 30.Administering both the MoCA and the MMSE in this trial will allowcomparisons of the utility within the setting of a clinical trial.

6.1.4 Neuropsychological Test Battery (NTB)

The neuropsychological battery from the Uniform Data Set (v3.0 Form C2)of the National Alzheimer's Coordinating Center (NACC) (Weintraub etal., 2009) will be administered to provide a more detailed assessment ofcognition. The battery includes brief measures of attention, processingspeed, executive function, episodic memory, and language. Exploratoryanalyses will classify participants as typical (i.e., prominent memoryimpairment) or atypical (i.e., relative sparing of memory) based uponpattern of performance on the neuropsychological test battery atbaseline. As described in the manual for test administration and scoring(Version 3.0, March 2015), Form C2 of the NACC UDS battery includes thefollowing measures:

6.1.4.1 Craft Story 21 Recall (Immediate and Delayed)

This is a measure of verbal episodic memory (Craft et al., 1996). Abrief story is read to the participant, who is then asked to retell itimmediately from memory. The primary measure of performance is thenumber of story units recalled. Delayed recall of the story is assessed20 minutes after immediate recall. Other neuropsychological measures areadministered during the delay interval (Range: 0-25 for each recalltrial).

6.1.4.2 Benson Complex Figure Copy & Recall

This test is a simplified form of the Rey-Osterrieth Complex Figure(Possin, Laluz, Alcantar, Miller, & Kramer, 2011). The purpose is toassess visuoconstructional and visual memory functions. In this test,the participant is presented with a figure composed of geometric shapes.The participant is then asked to reproduce (i.e. copy) the figure on thesame page. The accuracy of each shape and its placement are recorded.The primary measure of performance is the total score for copying thefigure (Range: 0-17). Approximately 10-15 minutes after the participantcopies the figure, visual memory is assessed by asking the participantto draw the figure again, from memory, on a blank page. The accuracy ofeach shape and its placement are recorded. The primary measure ofperformance is the total score for the delayed drawing of the Bensonfigure (Range: 0-17).

6.1.4.3 Multilingual Naming Test (MINT)

The MINT is a test of visual confrontation naming (Ivanova, Salmon, &Gollan, 2013). Participants are required to identify (i.e. name) linedrawings of objects. If the initial response is incorrect, semanticand/or phonemic cues are provided, as appropriate. Items are counted ascorrect if spontaneously named after semantic cuing (Range: 0-32).

6.1.4.4 Trail Making Test (Trails A and B)

The Trail Making Test is a test of processing speed and executivefunction. Trails A consists of 25 circles numbered 1 through 25distributed over a white sheet of paper. The participant is instructedto draw a line to connect the circles in ascending numerical order asquickly as possible (150 second maximum). Trails B consists of 25circles containing either numbers (1 through 13) or letters (A throughL) that are randomly distributed across the page, and participants areinstructed to connect the circles in alternating and ascending order(e.g., 1 to A; 2 to B). Performance is judged in terms of time tocomplete each trial. Time to complete Trails B (300 second maximum),adjusted for the time taken to complete Trails A to control forsensorimotor demands of the task, is a sensitive measure of executivefunction and working memory.

6.1.4.5 Verbal Fluency—Category Fluency

Category fluency assesses semantic memory and language fluency in whichparticipants name as many different exemplars of a given semanticcategory as rapidly as possible. Participants will be given 60 secondsto name exemplars in each of two categories: animals and vegetables.

6.1.4.6 Verbal Fluency—Phonemic Fluency

Phonemic Fluency is a measure of word generation that may be sensitiveto dysfunction in the dominant frontal lobe. Participants will be given60 seconds to name exemplars that begin with each of the two letters: Fand L.

6.1.4.7 Number Span Forward and Backward

Number Span assesses two different working memory constructs: ForwardNumber Span measures the capacity for retaining information very brieflyfor the purpose of repeating it exactly, while Backward Number Spanmeasures the ability not only to retain the information but also tomentally manipulate the numbers and recite them in reverse sequence.Numbers for both forward and backward span tests are presented withsequences ranging from 2 to 9 numbers. Two trials are administered ateach sequence length. Two scores are reported for each task: number ofcorrect trials and longest sequence repeated correctly prior to failingtwo consecutive trials of the same length.

6.2 Behavioral and Functional Measures 6.2.1 Clinical Dementia Rating(CDR) Scale—Sum of Boxes (SOB)

The CDR-SOB (Hughes, Berg, Danziger, Coben, & Martin, 1982) is avalidated composite rating of cognition and everyday functioning used inlongitudinal AD research which incorporates both informant input anddirect assessment of performance. It assesses through semi structuredinterview 3 cognitive domains including memory, orientation, andjudgement/problem solving and 3 everyday functional domains includingcommunity affairs, home and hobbies and personal care. There are 5levels of impairment from none CDR=0 to severe CDR=3. The individualdomain scores are added to create a sum of the box scores.

6.2.2 ADCS-Activities of Daily Living (ADL) Scale

The ADCS-ADL scale is a questionnaire developed by the ADCS to assessfunctional performance in participants with AD (Galasko et al., 1997).Scores range from 0 to 75, with higher scores indicating betterfunction.

6.2.3 Neuropsychiatric Inventory (NPI)

The NPI is a well-validated, reliable, multi-item instrument to assesspsychopathology in AD dementia based on the results of an interview withthe study partner (Cummings, 1997). The NPI evaluates both the frequencyand severity of 10 neuropsychiatric features, including delusions,hallucinations, agitation/aggression, dysphoria, anxiety, euphoria,apathy, disinhibition, irritability and lability, and aberrant motorbehavior, as well as evaluates sleep and appetite/eating disorders.Frequency assessments range from 1 (occasionally, less than once perweek) to 4 (very frequently, once or more per day or continuously).Severity assessments range from 1 (mild) to 3 (severe). The score foreach subscale is the product of severity and frequency and the totalscore is the sum of all subscales.

6.3 Modified Hachinski

This brief questionnaire, conducted by a clinician, incorporatesinformation regarding medical history, cognitive symptoms and featuresof stroke, reported by a study partner as well as the neurologicalexamination, and neuroimaging studies (Rosen, Terry, Fuld, Katzman, &Peck, 1980).

6.4 Sheehan Suicidality Tracking Scale (Sheehan STS)

The Sheehan STS (S-STS) is a prospective, patient self-reported orclinician administered rating scale that contains 16 questions to trackboth treatment-emergent suicidal ideation and behaviors (Sheehan, Alphs,et al., 2014; Sheehan, Giddens, & Sheehan, 2014). The S-STS will becompleted on a paper form at the site. At the screening visit, therecall period for completing the S-STS is 12 months prior; at all othervisits, the recall period for completing the S-STS is since the lastvisit.

Subjects who have an S-STS score >0 should be evaluated by theinvestigator. If the investigator determines that a subject is at riskof suicide or self-harm, appropriate measures to ensure the subject'ssafety and obtain mental health evaluation must be implemented. Thesubject must immediately be discontinued from the study. The eventshould be recorded as either an AE or SAE as determined by theinvestigator and reported within 24 hours to the Sponsor.

Study Example 3

Capsules containing 140 mg of troriluzole for use in the studiesdescribed in Example 1 and Example 2 are prepared in the followingproportions.

Composition of Troriluzole Capsules, 140 mg

Component Function Content per Capsule Drug Substance Active 140 mgingredient Mannitol Binder/Filler 60-90 mg MicrocrystallineBinder/Filler 20-40 mg cellulose + dicalcium phosphate¹ MicrocrystallineBinder/Filler 15-40 mg cellulose Hydroxypropyl Binder/Filler 5-10 mgcellulose Crospovidone Disintegrant 5-20 mg Colloidal silicon Glidant0.5-5 mg dioxide Magnesium stearate Lubricant 0.5-5 mg (vegetable grade)¹Provided as a 75:25 mixture of microcrystalline cellulose and anhydrousdicalcium phosphate.

Study Example 4

The T2 Protect AD trial has been conducted, which is a Phase 2/3,randomized, double-blind, placebo-controlled study evaluating theefficacy and safety of troriluzole in patients diagnosed withAlzheimer's disease of mild-to-moderate severity (Mini-Mental StateExamination [MMSE] scores of 14-24; mild: 20-24, moderate: 14-19). Thestudy data is summarized in Tables 10 to 15.

Troriluzole exhibited a numerical difference of a potential benefit atWeek 48 on the neuropsychiatric inventory (NPI), an exploratory measure,in participants with mild-to-moderate

AD. After 48 weeks, troriluzole treated participants (n=120) had a LSmean change from baseline of 2.3 points on the NPI score, versus 3.8points for placebo treated (n=125) participants, [difference −1.5, 95%Cl: −4.08, 1.10, p-value=0.258]. Troriluzole also exhibited numericaldifferences of a potential benefit at Week 48 on the NPI acrosssubgroups, including analyses consisting of only mild AD patients, onlymoderate AD patients, only ApoE4 positive patients, and only ApoE4negative patients. These findings are suggestive of a potentialbeneficial effect of troriluzole on reducing the frequency and severityof neuropsychiatric features in mild-to-moderate AD.

Moreover, a subgroup analysis consisting only of mild AD patientsrevealed that troriluzole exhibited numerical differences of a potentialbenefit at Week 48 on both the ADAS-cog co-primary measure, hippocampalvolumetric MRI secondary measure, and NPI exploratory measure. After 48weeks, troriluzole treated participants with mild AD (n=65) had a LSmean change from baseline of 4.2 points [95% Cl: 2.7, 5.7] on theADAS-Cog11 score, versus 4.9 points [95% Cl: 3.4, 6.4] for placebotreated (n=63) participants, [difference 0.7, 95% Cl: −1.4, 2.7,p-value=0.5233]. After 48 weeks, troriluzole treated participants withmild AD (n=48) had a LS mean percent deformation change from baselinehippocampal volume of −1.1% [95% Cl: −1.6, −0.6] versus −1.6% [95% Cl:−2.1, −1.0] for placebo treated (n=49) participants [difference-0.5%,95% Cl: −1.2, 0.3, p-value=0.2240]. After 48 weeks, troriluzole treatedparticipants with mild AD (n=62) had a LS mean change from baseline of2.1 points on the NPI score, versus 4.2 points for placebo treated(n=63) participants, [difference-2.1, 95% Cl: −5.99, 1.78,p-value=0.286]. These findings are suggestive of a potential beneficialand/or disease-modifying effect of troriluzole including improvingcognition, preserving hippocampal brain volumes, and reducingneuropsychiatric features in early stages of AD.

TABLE 10 Co-Primary ADAS-cog 11 at Week 48. Analysis Visit TypeStatistic Placebo Troriluzole Difference¹ ADAS-Cog Total Score Week 48Analysis Value N 127 119 Mean (SD) 324 (11.93) 31.5 (10.82) Median 30.030.0 Min, Max 3.0, 64.0 8.0, 66.0 Charge from Baseline N 127 119 Mean(SD) 8.1 (8.18) 0.8 (7.40) Median 5.0 0.0 Min, Max −27.0, 43.0 −10.0,37.0 Model Estimates LSMean (SE) 6.7 (0.08) 8.7 (0.70) 0.0 (0.93) DF256.24 95% Cl (5.4, 8.1) (5.3, 8.1 ). (−1.8, 1.8) P-Value 0.9809

TABLE 11 Co-Primary ADAS-cog 11 at Week 48 (Mild AD Patients Only).Analysis Visit Type Statistic Placebo Troriluzole Difference¹ ADAS-CogTotal Score Week 48 Analysis Value N 63 65 Mean (SD) 26.4 (8.16) 26.2(8.22) Median 26.0 26.0 Min, Max 13.0, 56.0 8.0, 49.0 Change fromBaseline N 63 65 Mean (SD) 5.0 (5.14) 3.9 (5.90) Median 5.0 4.0 Min, Max−5.0, 20.0 −10.0, 24.0 Model Estimates LSMean (SE) 4.9 (0.77) 4.2 (0.76)0.7 (1.02) DF 120.65 95% CI (3.4, 6.4) (2.7, 5.7) (−1.4, 2.7)

TABLE 12 Co-Primary CDR-SB at Week 48. Analysis Visit Type StatisticPlacebo Troriluzole Difference¹ CDR01-Sum of Boxes Week 48 AnalysisValue N 127 118 Mean (SD) 8.3 (3.05) 8.3 (3.24) Median 8.0 8.0 Min, Max2.0, 17.0 2.0, 17.0 Change from Baseline N 127 118 Mean (SD) 1.9 (2.38)1.9 (2.37) Median 2.0 2.0 Min, Max −8.0, 8.0 −4.5, 8.5 Model EstimatesLSMean (SE) 1.9 (0.21) 2.1 (0.21) −0.2 (0.28) DF 260.40 95% CI (1.5,2.3) (1.7, 2.5) ( −0.8, 0.3) P-Value 0.4474

TABLE 13 Co-Primary CDR-SB at Week 48 (Mild AD Patients Only). AnalysisVisit Type Statistic Placebo Troriluzole Difference¹ CDR01-Sum of BoxesWeek 48 Analysis Value N 63 62 Mean (SD) 7.1 (2.50) 7.1 (2.79) Median7.0 6.5 Min, Max 2.0, 12.0 2.0, 15.0 Change from Baseline N 63 62 Mean(SD) 1.5 (2.48) 1.4 (2.06) Median 1.0 1.0 Min, Max −8.0, 7.5 −4.5, 7.0Model Estimates LSMean (SE) 1.4 (0.30) 1.7 (0.29) −0.3 (0.40) DF 138.4995% CI (0.8, 1.9) (1.1, 2.2) ( −1.1, 0.5) P-Value 0.4347

TABLE 14 Volumetric Hippocampal MRI at Week 48. Analysis Visit TypeStatistic Placebo Troriluzole Difference¹ Hippocampal Volume Change Week48 Analysis Value N 90 87 Mean (SD) −1.1 (1.92) −1.1 (1.50) Median −1.0−0.9 Min, Max −6.4, 3.2 −5.5, 1.9 Model Estimates LSMean (SE) −1.1(0.18) −1.1 (0.18) 0.0 (0.26) DF 174.00 95% CI ( −1.5, −0.8) ( −1.4,−0.7) ( −0.6, 0.5) P-Value 0.8670

TABLE 15 Volumetric Hippocampal MRI at Week 48 (Mild AD Patients Only).Analysis Visit Type Statistic Placebo Troriluzole Difference¹Hippocampal Volume Change Week 48 Analysis Value N 49 48 Mean (SD)−1.6(2.11) −1.1 (1.61) Median −1.3 −0.9 Min, Max −6.4, 3.2 −5.5, 1.9Model Estimates LSMean (SE) −1.6 (0.27) −1.1 (0.27) −0.5 (0.38) DF 94.0095% CI ( −2.1, −1.0) ( −1.6, −0.6) ( −1.2, 0.3) P-Value 0.2240

With regard to safety and tolerability, treatment with troriluzole at adose of 280 mg once daily was relatively well tolerated and demonstrateda safety profile consistent with previous studies of troriluzole.

Throughout this application, various publications are referenced byauthor name and date, or by patent number or patent publication number.The disclosures of these publications are hereby incorporated in theirentireties by reference into this application in order to more fullydescribe the state of the art as known to those skilled therein as ofthe date of the invention described and claimed herein. However, thecitation of a reference herein should not be construed as anacknowledgement that such reference is prior art to the presentinvention.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures described herein. Such equivalents are considered tobe within the scope of this invention and are covered by the followingclaims. For example, it is intended in accordance with the presentinvention that combination therapy using a riluzole prodrug and othertherapeutic agents can be employed to treat ataxia and other associateddiseases. Further, riluzole prodrugs other than those specificallydisclosed in the description and Examples herein can be employed.Furthermore, it is intended that specific items within lists of items,or subset groups of items within larger groups of items, can be combinedwith other specific items, subset groups of items or larger groups ofitems whether or not there is a specific disclosure herein identifyingsuch a combination.

1-15. (canceled)
 16. A method of attenuating presynaptic glutamaterelease, the method comprising administering to a subject an effectiveamount of at least one compound having formula:

wherein R²³ is selected from the group consisting of H, CH₃, CH₂CH₃,CH₂CH₂CH₃, CH₂CCH, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂OH,CH₂OCH₂Ph, CH₂CH₂OCH₂Ph, CH(OH)CH₃, CH₂Ph, CH₂(cyclohexyl),CH₂(4-OH-Ph), (CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH, CH₂(3-indole),CH₂(5-imidazole), CH₂CO₂H, CH₂CH₂CO₂H, CH₂CONH₂, and CH₂CH₂CONH₂; or anenantiomer, diastereomer, hydrate, solvate, pharmaceutically acceptablesalt, or complex thereof.
 17. The method according to claim 16, whereinthe compound is selected from the group consisting of:(S)-2-amino-N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)propanamide;(R)-2-amino-N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)propanamide;(S)-2-amino-3-methyl-N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)butanamide;(R)-2-amino-3-methyl-N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)butanamide;(S)-2-amino-N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)-3-phenylpropanamide;(R)-2-amino-N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)-3-phenylpropanamide;(S)-2-amino-4-methyl-N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)pentanamide;(R)-2-amino-4-methyl-N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)pentanamide;(S)-2-amino-3-hydroxy-N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)propanamide;(R)-2-amino-3-hydroxy-N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)amino)-2-oxoethyl)propanamide;and2-(2-aminoacetamido)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide;or a pharmaceutically acceptable form thereof.
 18. The method of claim16, wherein the effective amount of at least one compound isadministered in a composition further comprising at least one excipient.19. The method of claim 16, wherein the attenuating presynapticglutamate release comprises an inhibitory effect on glutamate release,inactivation of voltage-dependent sodium channels, ability to interferewith intracellular events that follow transmitter binding at excitatoryamino acid receptors, or a combination thereof.